Darunavir/ritonavir Shows Safety and Superior Virological and Immunological Efficacy in Treatment-experienced Patients at 24 Weeks

By Ronald Baker, PhD

Although the advent of the protease inhibitors (PIs) has revolutionized the treatment of HIV infection, heavily treatment-experienced patients face increasing rates of virological failure. Studies suggest that at least 10% of HIV positive patients experience triple-class treatment failure. For some patients with prior 2-drug therapy, the rate of failure reaches 20%. In addition, these failure rates are increasing over time.

Clearly, new drugs that are active against both wild-type and resistant HIV are needed to improve treatment outcomes for this growing patient population.

Darunavir (Prezista, formerly TMC114) is a second generation PI that has demonstrated activity in vitro against both wild-type and multidrug-resistant HIV-1 strains. In June 2006, the U.S. Food and Drug Administration (FDA) granted "fast track" (accelerated) approval to darunavir for use with 100 mg ritonavir plus other antiretroviral agents for the treatment of HIV infection in adults.

The POWER 2 study (Performance of TMC114/ritonavir When Evaluated in Treatment-experienced Patients with PI Resistance) evaluated the efficacy and safety of 4 dosing regimens of darunavir boosted with low-dose ritonavir in patients who had experienced virological failure with 3 or more classes of antiretroviral drugs.

Following is a summary of the 24-week analysis of the POWER 2 study data, published in the March 30, 2007 issue of AIDS. 

Trial Design and Methods

Conducted at 45 sites in the U.S. and Argentina, POWER 2 was a multicenter, randomized, controlled, dose-finding Phase II study. Prior to patient randomization, the investigators selected an optimized background regimen (OBR) and a PI regimen based on genotypic resistance data and the patients’ prior treatment experience.

All study participants received an OBR that included at least 2 nucleoside reverse transcriptase inhibitors (NRTIs), with or without enfuvirtide (Fuzeon; T-20), but excluded non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Patients were randomly assigned to receive one of 4 darunavir/ritonavir dose regimens (400/100 mg or 800/100 mg once daily, or 400/100 mg or 600/100 mg twice daily; blinded for dose, not schedule) or control PI(s) (CPI) selected by the investigators.

Patients randomized to the CPI arm changed their entire regimen at baseline; those randomized to darunavir/ritonavir switched their PI to darunavir/ritonavir for 2 weeks and their optimized background regimen thereafter.

Enfuvirtide was included in the OBR of 120 (53%) darunavir/ritonavir recipients and 25 (47%) CPI recipients. Overall, 28% (40 of 145) of patients receiving enfuvirtide had prior experience with the drug.

Patients continued on their regimen unless they were withdrawn because of treatment-limiting toxicity or virological failure, which was defined as an HIV RNA decrease of < 0.5 log₁₀ copies/mL at week 8, < 1.0 log₁₀ copies/mL at or beyond week 12, or an increase of 0.5 log₁₀ copies/mL above nadir.

After the planned interim analyses (intent-to-treat), the primary efficacy analysis was amended to compare virological responses between darunavir/ritonavir doses and the CPI arm using a confirmed HIV RNA reduction from baseline of ≥ 1.0 log₁₀ copies/mL at week 24 (time to loss of virological response, or TLOVR analysis).

All patients receiving darunavir/ritonavir switched to the 600/100 mg twice-daily dose following the primary analysis cutoff date (February 2005).

Results

·         Of 583 patients screened, 294 were randomized and 278 were included in the intent-to-treat analysis.

·         The mean baseline HIV RNA was 4.7 log₁₀ copies/mL and the median baseline CD4 cell count was 106 cells/mm³.

·         Subjects’ HIV-1 isolates had a median of 3 primary PI mutations and a median fold change in lopinavir susceptibility of 80.

·         More patients in each darunavir/ritonavir dose group achieved ≥ 1.0 log₁₀ copies/mL reduction in HIV RNA compared with the CPI group (45%-62% vs 14%; P ≤ 0.003).

·         Patients taking darunavir/ritonavir twice daily had the greatest virological responses.

·         HIV RNA was < 50 copies/mL in 18%-39% of darunavir/ritonavir patients versus 7% of CPI patients (P < 0.001 for highest dose).

·         Mean CD4 cell counts increased by 59-75 cells/mm³ in the darunavir arms compared with 12 cells/mm³ in the CPI arm (P ≤ 0.005).

·         Overall adverse event rates were similar in the darunavir/ritonavir and CPI arms, with no significant differences among darunavir/ritonavir dose groups.

·         Discontinuation rates were 23% for darunavir/ritonavir versus 64% for CPI.

Adverse Events

Through 24 weeks, the incidence of adverse events of all grades regardless of cause was comparable in the darunavir/ritonavir and CPI arms. No relationship with darunavir/ritonavir dose was observed for any adverse event. When excluding enfuvirtide-associated injection-site reactions, the following adverse events (of any grade, any cause, and occurring in ≥ 10% of patients) occurred mostly at similar rates in the darunavir/ritonavir groups and the CPI arm: headache, nausea, diarrhea, fatigue, upper respiratory tract infection, insomnia, and pyrexia (fever).

Adverse events led to treatment discontinuation in 8% (18 of 225) of darunavir/ritonavir recipients and 4% (2 of 3) of CPI recipients.

Overall, 15% (33 of 225) of darunavir/ritonavir and 8% (4 of 53) of CPI patients reported one or more serious adverse event, the most common being pneumonia.

Six patients died during the study. All deaths were considered by the investigators to be unrelated (5) or doubtfully related (1) to the study medication.

In the 2 groups receiving darunavir/ritonavir twice daily, grade 3 or 4 triglyceride elevations were more common than in the other groups. However, the study authors noted that mean triglyceride levels decreased in all treatment groups: “Week-24 triglycerides reductions were 0.6-2.0 mmol/L for the darunavir/ritonavir groups compared with 0.5 mmol/L for the CPI group.”

The collection of long-term safety data from this study is ongoing.

Discussion

The study authors reported that 62% of patients who received darunavir/ritonavir 600/100 mg twice daily had at least a 1.0 log₁₀ copies/mL HIV RNA reduction, and 39% had HIV RNA < 50 copies/mL at week 24, “despite previous exposure to a median of 11 antiretrovirals and broad PI cross-resistance.”  Among those patients in the CPI arm, only 14% and 7%, respectively, of CPI recipients achieved the same endpoints.

“These differences were statistically significant and are clinically relevant,” wrote the authors. Further, they noted, “The study confirmed a dose-response relationship for virological efficacy with [darunavir/ritonavir]. These results, plus those from pharmacokinetic/pharmacodynamic analyses (pooled POWER 1 and 2) [1], validate the selection and regulatory approval of [darunavir/ritonavir] 600/100 mg twice daily for use in treatment-experienced patients.”

Results from this study and from POWER 1 [2] suggest that darunavir/ritonavir provides a valuable treatment option for patients with significant antiretroviral resistance, according to the authors.

The authors’ analyses show that when a greater number of active drugs were used in the patients’ optimized background regimen, virological outcomes were better in all the treatment groups. Patients receiving enfuvirtide for the first time experienced improved virological suppression rates. However, the investigators pointed out that overall responses to enfuvirtide-containing regimens were low in this study.

The incremental benefit of first-time enfuvirtide use in this study was more pronounced than that seen in the POWER 1 study, according to the authors. They wrote, “Taken together, these findings underscore the value of using 2 or more active antiretroviral drugs in treatment-experienced patients, and suggest a new treatment paradigm of achieving < 50 copies/mL in most patients with advanced HIV-1-treatment failure.”

The incidence of adverse events was similar in the darunavir/ritonavir and CPI arms in this 24-week analysis. The investigators noted no differences in the incidence of laboratory abnormalities, and they observed no dose-response relationship for adverse events or laboratory abnormalities.

Conclusions

Based on their findings, the study authors concluded that darunavir/ritonavir treatment resulted in greater virological and immunological responses in antiretroviral-experienced patients compared with CPI at 24 weeks. They wrote, “The combination of [darunavir/ritonavir] 600/100 mg twice daily with an optimized background regimen over 24 weeks was effective for those treatment-experienced HIV-1-infected patients whose virus carried multiple PI-resistance mutations.”

In conclusion, they stated, “These data suggest that [darunavir/ritonavir] will help to bridge the gap between the different treatment goals defined for treatment-experienced and treatment-naive patients, moving from previously accepted goals of partial and transient HIV-1 RNA reduction, with maintenance of immunological function, to a more effective and durable strategy of achieving complete viral suppression.”

03/30/07

Source

R Haubrich, D Berger, P Chiliade, and others (for the POWER 2 Study Group). Week 24 efficacy and safety of Darunavir (TMC114)/ritonavir in treatment-experienced HIV patients. AIDS 21(6): F11-F18 [Fast Track]. March 30, 2007.

References

1. A R Rinehart, P Lecocq, P McKenna, and others. Predicted phenotypic resistance in routine clinical samples between 1998 and 2003. Antiviral Therapy 9: S90. 2004

2. 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]. AIDS 21(4): 395-402. February 19, 2007.