Although the widespread use of potent HAART has significantly reduced mortality and morbidity among HIV positive individuals, there is a continuing need for the development of new anti-HIV drugs that are safe, provide sustained virological suppression, and exhibit a favorable resistance profile.

The U.S. Food and Drug Administration (FDA) granted “fast track” (accelerated) approval to the HIV protease inhibitor (PI) darunavir (Prezista) boosted with ritonavir (DRV/r) in June 2006 for use in combination with other antiretroviral agents for the treatment of HIV infection in adults. In September 2000 the FDA granted accelerated approval to the fixed-dose combination of the two PIs lopinavir and ritonavir (LPV/r; Kaletra) in capsule and oral solution form for use in combination with other antiretroviral agents. The FDA approved LPV/r in tablet form in October 2005.

The US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents list LPV/r, in combination with other anti-HIV drugs, as a preferred regimen for initial antiretroviral therapy in HIV positive adults who are treatment-naive. The drug is also used extensively in treatment-experienced HIV patients who have developed resistance to other PI- or NNRTI-based treatment regimens.

Published in the July 7, 2007 issue of The Lancet, the current study, called TITAN (TMC114/r In Treatment-experienced patients Naive to lopinavir) [1], evaluated the efficacy and safety of ritonavir-boosted darunavir in HIV patients naive to lopinavir who -- although not naïve to other antiretrovirals -- were not heavily treatment-experienced. A summary of the data from this published study is posted on this website.

Data from the TITAN Phase 3 trial was also presented in an oral abstract session at the 4^th IAS conference in Sydney (July 22-25, 2007) [2]. Following is a summary of that presentation by the trial’s lead investigator, Dr. Jose Valdez-Madruga of Treinamento DST/AIDS, Mariana-São Paulo, Brazil.

The objective of TITAN was to evaluate darunavir/ritonavir in a broad range of treatment-experienced HIV patients that reflect a “real-life” clinical population, and that also included patients undergoing treatment interruption. “The main aim,” according to the study authors, “was to show non-inferiority of darunavir/ritonavir 600/100 mg twice daily compared with lopinavir/ritonavir 400/100 mg twice daily, in terms of virological response, with both agents given in addition to an individually optimized background regimen.”

The authors noted that they chose to compare darunavir/ritonavir with lopinavir/ritonavir, “because of [lopinavir/ritonavir] efficacy and safety in protease inhibitor-experienced patients [that has been shown] in several randomized controlled trials” [3-6].

TITAN is an ongoing, international, randomized, controlled, open-label, 96-week Phase III trial that is being conducted at 159 medical centers in 26 countries. The primary endpoint of the trial was non-inferiority of DRV/r to LPV/r in confirmed virological response (VL <400copies/mL, TLOVR) at 48 weeks. In case of non-inferiority, DRV/r superiority was a secondary endpoint.

Treatment-experienced, LPV-naive, HIV-1-infected patients (VL >1,000 copies/mL) on stable HAART or off-treatment for >/=12wks were randomized to receive DRV/r 600mg/100mg bid or LPV/r 400mg/100mg bid plus OBR (>/=2 NRTIs/NNRTIs).

Results

• 595 patients (of 785 screened) were randomized and treated (298 with darunavir/ritonavir and 297 with lopinavir/ritonavir) and were included in the ITT analysis.
  
  
• At week 48, significantly more patients in the darunavir/ritonavir arm than in the lopinavir/ritonavir arm achieved HIV RNA levels less than 400 copies/mL (77% vs 68%) and <50 copies/mL (71% vs 60%), respectively, in an ITT-TLOVR analysis.
  
  
• The lower limit of the 95% CI for the difference in response between DRV/r and LPV/r did not exceed −12%, establishing non-inferiority, and did not include 0, thereby confirming superiority of DRV/r over LPV/r (p=0.008).
  
  
• Compared with those receiving lopinavir/ritonavir, fewer patients with virological failure treated with darunavir/ritonavir developed primary PI mutations (21% [n=6] vs 36% [n=20]) or NRTI-associated mutations (14% [n=4] vs 27% [n=15]).
  
  
• The median change from baseline in CD4 cell count at week 48 was similar in the 2 groups (NC=F): 88 cells/mm³ with darunavir/ritonavir and 81 cells/mm³ with lopinavir/ritonavir.
  
  
• More patients withdrew from the lopinavir/ritonavir arm than the darunavir/ritonavir group.
  
  
• 11% of patients in the lopinavir/ritonavir group discontinued treatment due to virological failure, compared with 1% in the darunavir/ritonavir group.
  
  
• Safety data were generally similar between the groups.
  
  
• Grade 3 or 4 adverse events (AEs) occurred in 80 patients (27%) in the darunavir/ritonavir group and 89 (30%) in the lopinavir/ritonavir group.
  
  
• AEs with DRV/r were diarrhea (31.9%), nausea (18.5%) and nasopharyngitis (12.4%), which occurred in 41.8%, 20.9% and 11.1% of LPV/r patients, respectively.
  
  
• Discontinuations due to AEs were low (0.7% for rash in the DRV/r arm).
  
  Table

^*p<0.01 vs LPV/r

Conclusions

In conclusion, the study authors stated, “The results of this large Phase III trial in lopinavir-naive, HIV-infected, treatment-experienced patients showed that darunavir/ritonavir was non-inferior to lopinavir/ritonavir, as determined by the primary endpoint of less than 400 copies/mL of HIV RNA at week 4” [1].

Furthermore, the authors stated, “Results of a secondary analysis showed that darunavir/ritonavir was superior to lopinavir/ritonavir [in virological response] at this time point [48 weeks]” [1].

“Importantly,” they continued, “the population was specifically selected to include patients with less advanced disease than those studied in the POWER 1 and 2 trials, in which darunavir had already shown superiority to lopinavir and other available protease inhibitors” [7-9].

07/27/07

References

1. J V Madruga, D S Berger, M  McMurchie, and others (TITAN study group). Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. The Lancet 370 (9581): 49-58. July 7, 2007.

2. J Valdez-Madruga, D S Berger, M McMurchie, and others (TITAN study group). Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naïve, treatment-experienced patients: a randomised, controlled phase III trial (TITAN). 4^th IAS Conference. July 22-25, 2007. Sydney, AU. Abstract (oral) TuAb101.

3. E DeJesus, A LaMarca, M Sension, and others. The CONTEXT study: efficacy and safety of GW433908/r in PI-experienced subjects with virological failure (24 week results). 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA. 2003. Abstract 178.

4. M Johnson, B Grinsztejn, C Rodriguez C, and others. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 19: 685-694. April 29, 2005.

5. R B Pollard, M A Thompson, C B Hicks, and others. Phase 3 comparison of lopinavir/ritonavir vs investigator-selected protease inhibitors in single PI-experienced, NNRTI-naive patients: 48-week results of study M98-888. Proceedings of the 7th International Congress on Drug Therapy in HIV Infection, Glasgow, UK. 2004. Abstract PL3.2.

6. C A Benson, S G Deeks, S C Brun, and others. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. Journal of Infectious Diseases 185:  599-607. March 1, 2002.

7. B Clotet, N Bellos, J M Molina, and others (POWER 1 and 2 study Groups). 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. The Lancet  369: 1169-1178. April7, 2007.

8. C Katlama, R Esposito, J M Gatell, and others. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395-402. February 19, 2007.

9. R Haubrich, D Berger, P Chiliade, and others. Week 24 Efficacy and Safety of TMC114/ritonavir in Treatment-experienced HIV Patients. AIDS 21: F11-18. March 30, 2007.

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