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Second Trial of Darunavir Monotherapy Seems Less Convincing
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Compared with a European trial of darunavir/ritonavir monotherapy versus standard triple therapy [1], a French trial of the same maintenance tactic proved less convincing for three reasons: in one of two 48-week analyses, darunavir monotherapy was "not noninferior" to darunavir triple-therapy maintenance; there were three virologic failures in people taking darunavir monotherapy and none in the standard-therapy arm; and virologic response analyses used a viral load threshold of 400 copies instead of 50 copies [2].
In the European MONET trial [1], already reported by NATAP, sub-50-copy response rates at 48 weeks were 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, sub-50 response rates were almost identical--84.3% with monotherapy and 85.3% with standard therapy. Two people in each group had a sustained rebound above 400 copies.
The French MONOI trial (ANRS 136) enrolled 242 people with a viral load below 400 copies for at least 18 months and fewer than 50 copies at entry [2]. No one had taken darunavir before, and no one had a record of virologic failure.
During an 8-week induction phase, everyone took darunavir/ritonavir (600/100 mg twice daily) plus two nucleosides. The 225 people who maintained viral suppression were randomized to continue twice-daily darunavir/ritonavir plus two nucleosides (n = 113) or to switch to twice-daily darunavir/ritonavir monotherapy (n = 112). (MONET trial participants took darunavir/ritonavir once daily [1].)
Three quarters of MONOI participants were men. Median age was about 46 years, and starting CD4 counts were 582 in the triple-therapy arm and 585 in the monotherapy group. While 73% in the triple-drug group entered the trial taking a PI, 64% in the monotherapy arm were taking a PI-based regimen. About 20% in each group were taking a nonnucleoside-based combination, and the rest were taking three nucleosides.
The MONOI team defined failure as consecutive viral loads above 400 copies or treatment modification or discontinuation. In a per-protocol analysis, 99% in the triple-drug arm and 94.1% in the monotherapy arm met those response criteria by week 48. Those results indicated that darunavir/ritonavir maintenance monotherapy is not inferior to darunavir-based triple therapy in people like those in this trial.
However, in the intention-to-treat population (the 225 people randomized), 92.0% assigned to triple therapy versus 87.5% assigned to monotherapy met response criteria by week 48. Comparing those response rates, statisticians found that the lower limit of the 90% confidence interval for the difference between arms, -11%, was below the -10% set as the lower bound for proving noninferiority.
Christine Katlama (Pitie-Salpetriere Hospital, Paris) counted 9 failures in the triple-therapy group and 14 in the monotherapy arm. Six of the triple-therapy failures were treatment modifications and 3 were withdrawals. Eight of the monotherapy failures were treatment modifications, 3 were withdrawals, and 3 were virologic failures. The first monotherapy patient with virologic failure had a viral load of 2722 copies at week 8 and a low 24-hour darunavir concentration (1120 ng/mL). The second person had a viral load of 411 copies at week 24 and an adequate 24-hour concentration (3480 ng/mL). The third person had a load of 484,569 copies at week 32 and stopped treatment. At week 48, 92.0% in the triple-therapy group and 86.6% in the monotherapy group had a viral load under 50 copies.
The only major difference between regimens in serious adverse events involved central nervous system (CNS) problems--3 in the monotherapy group and 1 in the triple-therapy group. The 3 CNS disorders in the monotherapy arm included 1 case of HIV encephalitis and 1 case of "neurologic symptoms" possibly related to HIV. Both were possibly related to darunavir/ritonavir.
Unlike the MONET investigators [1], the French MONOI team reported viral loads in cerebrospinal fluid (CSF). They found 2 people with undetectable HIV RNA in blood plasma but detectable virus in CSF. An earlier study of atazanavir/ritonavir monotherapy found discordant viral loads in blood versus CSF and in blood versus semen [3]. Ensuring antiretroviral penetration of compartments like the brain and genital tract should precede clinical use of boosted-PI 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. 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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