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Once-Daily Darunavir Monotherapy Effective for 48 Weeks After Viral Control
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
In people with a viral load under 50 or 400 copies while taking a standard antiretroviral regimen, switching to once-daily darunavir/ritonavir alone kept HIV under control as well as darunavir/ritonavir plus two nucleosides in two large randomized trials [1,2]. Resistance rates were low and similar in the two treatment arms. Jose Arribas (Hospital La Paz, Madrid) presented results of the first darunavir monotherapy trial, MONET, at a July 21 session of the IAS Conference [1]. Results of the French MONOI trial will be detailed on July 22.
Most earlier monotherapy studies involved lopinavir/ritonavir. A systematic review of six randomized controlled trials of lopinavir/ritonavir found a higher risk of failure with monotherapy than with a standard regimen (33.2% versus 22.9%, pooled odds ratio 1.48, 95% confidence interval 1.02 to 2.13, P = 0.037) [3]. But among people who successfully controlled HIV after restarting nucleosides, failure rates did not differ between monotherapy groups and standard-regimen groups (26.9% versus 22.9%, odds ratio 1.05, P = 0.81). The authors of this analysis concluded that "the majority of patients with prolonged viral suppression on HAART can successfully be treated with protease inhibitor monotherapy."
MONET trial researchers recruited 256 Europeans with a viral load below 50 copies for at least 6 months while taking a standard nonnucleoside regimen (43%) or protease inhibitor (PI) regimen (57%) [1]. No one could have darunavir experience, and no one could have a history of virologic failure. The MONET team randomized 127 people to switch to 800/100 mg of darunavir/ritonavir once daily alone and 129 to start once-daily darunavir/ritonavir plus two nucleosides.
Most study participants were white (91%), and most (81%) were men. Median CD4 count stood at 575 and median age at 43 years. People randomized to monotherapy had taken antiretrovirals longer (average 7.4 versus 6.4 years), and more of them had hepatitis C virus infection (19% versus 11%).
Nine people in each treatment group stopped taking their assigned regimen. No new or unexpected treatment-related problems arose during the trial.
Defining failure as consecutive viral loads above 50 copies, the investigators calculated a 48-week virologic response rate of 86.2% with monotherapy and 87.8% with triple therapy in a per-protocol analysis that excluded 10 people with protocol violations and counted drug switches as failures. In an intent-to-treat analysis that included the 10 protocol violators, response rates were almost identical--84.3% with monotherapy and 85.3% with standard therapy. And in an analysis that allowed switching, response rates were 93.5% with monotherapy and 95.1% with triple therapy. All of these comparisons indicated that darunavir/ritonavir monotherapy is not inferior to darunavir/ritonavir plus two nucleosides in people who start one of these regimens with a viral load under 50 copies.
Eleven people in the monotherapy group and 7 in the triple-therapy group had two transient viral load readings above 50 copies, and 2 people in each group had a sustained viral load rebound above 400 copies. The investigators attributed most temporary or sustained rebounds to poor adherence or to emergence of other illnesses that may affect HIV load. At the last study visit, 124 of 127 people randomized to monotherapy and 126 of 129 randomized to triple therapy had a viral load under 50 (97.6% and 97.7%).
Arribas and coworkers searched for resistance mutations any time someone's viral load rose above 50 copies. Most of these 50-plus readings were transient blips. As already noted, people in the monotherapy group had more blips, a result reflecting findings in randomized trials of lopinavir/ritonavir monotherapy. All told, the MONET team had successful genotypes on 22 people taking monotherapy and 13 taking triple therapy. A new resistance mutation emerged in only 1 person in each study group. The M184V lamivudine/emtricitabine mutation and one primary PI mutation arose in 1 person taking darunavir plus two nucleosides; one primary PI mutation and one darunavir-related mutation evolved in a person on monotherapy. Neither of the two people with new PI mutations had phenotypic evidence of decreased viral susceptibility to darunavir.
An important question that remains to be addressed is how well darunavir/ritonavir monotherapy controls HIV replication in sequestered sites like the central nervous system and genital tract. In a trial of atazanavir/ritonavir monotherapy, 3 of 20 people with a plasma load below 50 copies had levels above 100 copies in cerebrospinal fluid, and 2 of 15 with undetectable HIV in plasma had detectable virus in semen [4]. The MONET team did not report cerebrospinal or seminal viral loads with darunavir/ritonavir monotherapy.
References
1. Arribas J, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract TUAB106-LB.
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.
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. Vernazza P, Daneel S, Schiffer V, et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) trial. AIDS. 2007;21:1309-1315.
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