Boosted Darunavir (Prezista) Monotherapy Works Well as Maintenance Therapy, but Not So Well As Initial Regimen

Boosted Darunavir (Prezista) Monotherapy Works Well as Maintenance Therapy, but Not So Well as Initial Regimen

SUMMARY: Protease inhibitor monotherapy using ritonavir-boosted darunavir (Prezista) was able to keep HIV suppressed when used as a simplified maintenance regimen in patients who achieved undetectable viral load on combination antiretroviral therapy (ART), according to the latest results from the MONET trial reported this month at the 12th European AIDS Conference (EACS 2009). However, another study of darunavir/ritonavir monotherapy as a first-line regimen was stopped early because a significant proportion of patients did not achieve adequate viral suppression.

By Liz Highleyman

Standard antiretroviral therapy regimens consisting of a combination of drugs, usually ether a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

But researchers have explored monotherapy using potent next-generation boosted protease inhibitors (the small boosting dose of ritonavir is not counted as a separate drug) in an effort to improve convenience and reduce pill burden, cost, and NRTI and NNRTI side effects and long-term toxicities.

Darunavir/ritonavir Maintenance

D. Ripamonti and colleagues presented the latest findings from the MONET study. As previously reported at the International AIDS Society (IAS) conference this past summer, the European MONET study included 256 patients taking a standard 3-drug regimen with a viral load below 50 copies/mL for at least 6 months and no history of virological treatment failure.

Most participants were men (81%) and white (91%), with a median age of 43 years at baseline. They had been on ART for an average of 6-7 years and had well-controlled HIV disease, with a median CD4 cell count of 575 cells/mm3.

Participants were randomly assigned to switch to 800/100 mg once-daily darunavir/ritonavir, either as monotherapy or as part of a standard ART regimen in combination with 2 NRTIs. At baseline, 57% were taking a protease inhibitor-based regimen and 43% were taking a NNRTI.

Results

At 48 weeks, darunavir/ritonavir monotherapy was non-inferior to darunavir/ritonavir combination therapy, with similar proportions of patients in both arms achieving HIV RNA suppression:

	Intention-to-treat (ITT) analysis, HIV RNA < 50 copies/mL: 84.3% vs 85.3%, respectively (delta -1.0%).
	Per-protocol TLOVER (time-to-loss-of-virological response) analysis, "switch = failure," HIV RNA < 50 copies/mL: 86.2% vs 87.8%, respectively (delta -1.6%).
	Per-protocol, HIV RNA < 200 copies/mL: 88.6% vs 91.9% (delta -3.3%)
	ITT, switch not counted as failure, HIV RNA < 50 copies/mL: 93.5% vs 93.1% (delta -1.6%);

30 patients experienced treatment failure according to predefined criteria.

Among 20 patients who did not maintain viral suppression < 50 copies/mL, 11 (9%) experienced a confirmed viral "blip" (transient, usually small increase).

All but 1 of this group regained viral suppression by week 48.

9 patients who did not maintain HIV RNA < 50 copies/mL stopped or changed treatment during the study.

7 of this group had a viral load < 50 copies/mL at the end of the study.

Protease inhibitor and darunavir-specific resistance mutations were rare among patients who experienced treatment failure.

Treatment was generally well tolerated.

Darunavir/ritonavir Induction

In another presentation at the same conference session, Pedro Cahn from Fundacion Huesped in Buenos Aires, Argentina, described findings from study TMC114-C227, which looked at boosted darunavir as an initial regimen, or induction therapy.

This Phase 2 trial was designed to start with 11 treatment-naive patients with HIV RNA 10,000-100,000 copies/mL who would initiate first-line ART using 800/100 mg once-daily ritonavir-boosted darunavir. The plan was to then add more patients with a broader range of viral loads.

As it happened, the study had difficulty recruiting even the first cohort due to strict exclusion criteria, including the narrow viral load range and no pre-existing relevant resistant mutations; only 7 patients were enrolled. Ultimately, the trial was halted prematurely after half the initial participants failed to achieve and maintain adequate HIV suppression.

Results

	By 4 weeks, all 7 participants had a 10-fold or greater decline in HIV RNA.
	By 8 weeks, 57% (4 of 7) had viral load < 400 copies/mL.
	By 24 weeks, just 50% -- 2 of the remaining 4 participants -- had HIV RNA < 50 copies/mL.
	All participants were able to achieve full viral suppression when they subsequently added NRTIs.
	At week 12, the mean CD4 cell gain was about 165 cells/mm3.
	Genotypic testing identified no emergent protease inhibitor or darunavir resistance mutations.
	Again, treatment was generally well tolerated.

"All patients achieved >1 log10 HIV-1 RNA reduction by week 4 but complete viral suppression was not consistently achieved on induction monotherapy," the investigators concluded.

Though they stated that darunavir/ritonavir monotherapy as a first-line regimen "cannot be recommended in antiretroviral-naive patients," Cahn noted that the study was too small to produce definitive results.

Taken together, these findings suggest that ritonavir-boosted darunavir monotherapy does a good job at keeping viral load suppressed, but may have trouble suppressing it in the first place without help from other drug classes.

Current U.S. antiretroviral therapy guidelines and the newly updated European treatment guidelines do not include protease inhibitor monotherapy as a preferred option, but allow that it may be considered for specific patients with suppressed viral load who have trouble tolerating other classes of drugs.

11/24/09

References

D Ripamonti, J Arribas, F Pulildo, and A Hill. Non-inferior efficacy shown across different efficacy endpoints in the MONET trial of darunavir/ritonavir monotherapy. 12th European AIDS Conference. Cologne, Germany. November 11-13, 2009. Abstract PS4/1.

P Patterson, A Krolewiecki, P Tomaka, P Cahn, and others. A phase II, open-label trial in treatment-naive, HIV-1-infected subjects who received DRV/RTV as induction monotherapy. 12th European AIDS Conference. Cologne, Germany. November 11-14, 2009. Abstract PS4/4.