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  AIDS 2010
18th International AIDS Conference (IAC)
July 18-23 2010
Vienna, Austria
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Darunavir/Ritonavir Monotherapy Fails Primary
Noninferiority Test at MONET Week 96

  XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
Maintenance treatment with darunavir/ritonavir monotherapy failed to meet noninferiority criteria for virologic efficacy when compared with standard triple therapy in the primary week-96 analysis of the international MONET trial [1]. In a secondary analysis not counting regimen switches as failures, monotherapy did prove noninferior to triple therapy.
Once-daily darunavir/ritonavir has emerged as the most promising monotherapy candidate for people who reach and maintain an undetectable viral load with a standard triple regimen. After 48 weeks in MONET, a time-to-loss-of-virologic response (TLOVR) analysis determined 86.2% of study participants taking monotherapy versus 87.8% taking triple therapy had a viral load below 50 copies [2]. Those rates meant that monotherapy was noninferior to triple therapy at week 48.
MONET involved 256 adults with a viral load below 50 copies for at least 6 months while taking two nucleosides plus either a nonnucleoside or a ritonavir-boosted protease inhibitor (PI). Researchers randomized 127 people to switch to darunavir/ritonavir monotherapy at a dose of 800/100 mg once daily and 128 people to take the same dose of darunavir/ritonavir plus two nucleosides selected for maximal efficacy. Study participants could not have used darunavir before and could not have an earlier virologic failure.
Both treatment groups had a median age of 43 years, about 80% of study participants were men, and about 90% were white. Median CD4 count when MONET began stood at 571 in the monotherapy arm and 579 in the triple-therapy arm. The monotherapy group had taken antiretrovirals for an average 7.4 years, compared with 6.4 years in the triple-therapy group. Twenty-four people (19%) assigned to monotherapy and 15 (12%) assigned to triple therapy had antibody to hepatitis C virus (HCV), while 20 (16%) taking monotherapy and 12 (9%) taking triple therapy had a history of injection drug use.
MONET''s primary endpoint is a TLOVR analysis in which switching from the assigned regimen counts as failure. People with a confirmed viral load above 50 copies who got their viral load back below 50 at week 96 would be counted as virologic failures, even if they did not switch or intensify their regimen.
In this primary analysis at 96 weeks, 74.8% on darunavir/ritonavir monotherapy and 80.6% on triple therapy had a viral load before 50 copies. The difference between treatment arms was -5.8% and the 95% confidence interval [CI] -16.0% to +4.4%. Those numbers mean monotherapy was "not noninferior" to standard triple therapy. In other words, monotherapy was inferior by this analysis. In an analysis that did not count switching or regimen intensification as failure, 92.1% taking monotherapy and 90.7% taking triple therapy had a week-96 viral load below 50 copies. In this analysis, monotherapy was not inferior to triple therapy.
In both treatment arms, the MONET team noted, “most elevations in HIV RNA were low level (50-200 copies/mL), and patients were re-suppressed to below 50 copies/mL at week 96, either on the original randomised treatment or with intensified treatment.”
Univariate analysis identified two predictors of a week-96 viral load below 50 copies in the TLOVR analysis. HCV antibody positivity quadrupled the risk of failure to meet this endpoint (odds ratio [OR] 4.25, 95% CI 1.09 to 9.64, P < 0.0001), as did a history of injection drug use (OR 4.21, 95% CI 1.90 to 9.32, P = 0.0004). In multivariate analysis, HCV positivity emerged as the only independent predictor of failure to have a week-96 viral load under 50 copies in the TLOVR analysis (OR 4.32, 95% CI 2.06 to 9.17, P < 0.0001). A week-96 TLOVR switch=failure analysis limited to 39 people with HCV antibody calculated a 43.5% response rate with monotherapy (n = 24) versus 73.3% in the comparison arm (n = 15), and in a switch=included TLOVR analysis 93.0% achieved <50 at week 96 who were HCV-antibody positive receiving triple therapy (DRV+2NRTI vs 79% receiving DRV/r monotherapy. The presenter noted that HCV antibody positive patients were 90% IV drug users, with significantly worse adherence.
Among people with a detectable viral load at some point in 96 weeks, a darunavir-associated resistance mutation (L33F) emerged in 1 person taking monotherapy, while the M184V lamivudine/emtricitabine mutation and three PI mutations (I54V, V82T, and L90M) emerged in 1 person in the triple-treatment group. No one in the study had evidence of decreased viral susceptibility to darunavir.
Rates of overall adverse event and grade 2 to 4 psychiatric and central nervous system adverse events were similar in the two study arms. Rates of some grade 3 or 4 lab abnormalities were higher with monotherapy than triple therapy: elevated alanine aminotransferase in 8 (6.3%) on monotherapy and 3 (2.4%) on triple therapy, elevated aspartate aminotransferase in 5 (3.9%) on monotherapy therapy and 2 (2.4%) on triple therapy, elevated total cholesterol in 14 (11.0%) on monotherapy and 5 (3.9%) on triple therapy, and elevated triglycerides in 4 on monotherapy (3.2%) and 1 (0.8%) on triple therapy.
PI penetration of genital and central nervous system compartments remains a concern with monotherapy strategies. Swiss investigators continued to track viral loads in plasma and cerebrospinal fluid (CSF) in 27 patients with an undetectable load in both for at least 1 year while taking ritonavir-boosted lopinavir, atazanavir, or indinavir [3]. Twenty-three people agreed to spinal taps to check for HIV in CSF. After median follow-up of 4.8 years, HIV could be detected in 9 of 27 people, including 4 with rebounds in plasma and CSF, 2 with rebounds only in plasma, and 3 with rebounds only in CSF. The Swiss investigators recommended regular lumbar punctures for people who stay on a PI monotherapy regimen.
An earlier study found good darunavir CSF penetration in 8 people taking darunavir/ritonavir as part of a standard regimen [4]. An 18-patient study confirmed that result [5]. MONET investigators have not yet reported CSF penetration results.
1. Rieger A, Banhegyi D, Schmidt W, et al. The MONET trial 96 week analysis: darunavir/ritonavir monotherapy versus DRV/r + 2NRTIs, for patients with HIV RNA < 50 copies/mL at baseline. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract THLBB209.
2. Arribas JR, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24:223-230.
3. Kahlert C, Witteck A, Gutmann C, et al. Late treatment failures in CSF in patients on long-term maintenance ART with ritonavir-boosted PI monotherapy. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract LBPE20. 4. Yilmaz A, Izadkhashti A, Price RW, et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals. AIDS Res Hum Retroviruses. 2009;25:457-461.
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.