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MONET Paints Noninferiority Picture With Darunavir/Ritonavir Monotherapy
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12th European AIDS Conference, November 11-13, 2009, Cologne, Germany
Mark Mascolini
Early maintenance therapy with darunavir/ritonavir alone proved noninferior to darunavir/ritonavir plus two nucleosides across an array of 48-week analyses in the MONET trial [1]. The results should hearten monotherapy enthusiasts because the investigators used a standard-of-care sub-50-copy primary endpoint and because study participants took darunavir/ritonavir in a once-daily 800/100-mg dose, instead of twice daily as in the MONOI monotherapy trial [2] or in monotherapy studies of lopinavir/ritonavir [3].
MONET recruited people with no virologic failure on their charts and with a viral load under 50 copies on their current regimen. Of the 256 study participants from across Europe (and Israel), 57% were taking a protease inhibitor (PI) and 43% a nonnucleoside when MONET investigators randomized them to darunavir/ritonavir alone or to those PIs plus two nucleosides.
The primary efficacy endpoint of MONET was a viral load under 50 copies at week 48 in a time-to-loss-of-virologic response (TLOVR) per-protocol analysis with drug switches counted as failures. Twelve people did switch or discontinue their assigned regimen, and 30 met failure criteria, but the primary analysis found little difference between response to monotherapy (86.2%) and response to triple therapy (87.8%) (delta [difference] -1.6%, 95% confidence interval [CI] -10.1% to +6.8%). Those results meant darunavir/ritonavir alone was noninferior to darunavir/ritonavir plus nucleosides at 48 weeks in this population.
Darunavir/ritonavir monotherapy also proved noninferior to triple therapy with those PIs in four subanalyses:
· Intention-to-treat analysis: 84.3% versus 85.3% (delta -1.0%, 95% CI -9.9% to +8.9%)
· 200-copy endpoint: 91.9% versus 88.6% (delta -3.3%, 95% CI -10.7% to +4.2%)
· Switch not counted as failure: 93.5% versus 93.1% (delta -1.6%, 95% CI -8.9% to +5.5%)
· Virologic endpoints only: 90.6% versus 92.3% (delta -3.2%, 95% CI -9.5% to +3.1%)
Among 127 people randomized to monotherapy, 107 (84%) reached and maintained a viral load below 50 copies throughout the trial's 48 weeks. Of the 20 people who did not sustain a sub-50 load, 11 (9%) had a confirmed viral blip. Ten of those 11 people pushed their viral load back under 50 copies by week 48. The eleventh person had a viral load of 810 copies at week 48. The 9 remaining people who did not sustain a sub-50 load stopped or changed treatment during the study. Seven of those 9 had a viral load under 50 copies at the last study visit.
In a separate report, MONET researchers saw little resistance after failure in either treatment arm [4]. The MONET team successfully genotyped virus from 38 of 63 people with a viral load above 50 copies--24 people in the monotherapy arm and 14 in the triple-therapy arm. One IAS-USA-defined PI mutation and one darunavir-associated mutation (L33F) emerged in one person taking darunavir/ritonavir monotherapy, but that person's virus remained susceptible to darunavir. Pre-existing mutations re-emerged in one person in the triple-therapy arm.
Several questions remain about darunavir/ritonavir monotherapy, including:
1. Whether it will hold up in most people over a few years so patients can avoid the complications of resuming nucleosides, then possibly wanting to stop them again
2. Whether markers can pick out people who will or will not respond to monotherapy
3. Whether darunavir/ritonavir monotherapy holds any advantage over the 3-in-1 once-daily pill Atripla (efavirenz, tenofovir, plus emtricitabine)
4. Whether long-term side effects differ between darunavir/ritonavir monotherapy, Atripla, and other current or imminent first-line therapies
5. Whether darunavir/ritonavir penetrates genital and central nervous system compartments
An 18-patient study reported earlier this year found that darunavir taken as part of a standard regimen achieved cerebrospinal fluid levels exceeding the 50% inhibitory concentration in all 29 samples analyzed [5]. Seventeen of these people were taking darunavir/ritonavir twice daily.
References
1. Ripamonti D, Arribas J, Pulildo F, Hill A. Non-inferior efficacy shown across different efficacy endpoints in the MONET trial of darunavir/ritonavir monotherapy. 12th European AIDS Conference. November 11-13, 2009. Cologne, Germany. Abstract PS4/1.
2. Katlama C, Valentin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136 C. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WELBB102. http://www.natap.org/2009/IAS/IAS_45.htm.
3. Bierman WF, van Agtmael MA, Nijhuis M, Danner SA, Boucher CA. HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS. 2009;23:279-291.
4. Nelson M, Arribas J, Pulido F, Hill A, Moecklinghoff C. Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir. 12th European AIDS Conference. November 11-13, 2009. Cologne, Germany. Abstract PE3.4/1.
5. Letendre S, Rossi S, Best B, et al. Darunavir concentrations in CSF exceed the median inhibitory concentration. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract A-1312.
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