At week 48, the median CD4 cell count was 574 cells/μl [interquartile range (IQR) 452–825, median increase 36 cells/μl, IQR −71–100] on darunavir/r triple therapy and 621 cells/μl (IQR 481–778, median increase 6 cells/μl, IQR −53–93) on darunavir/r monotherapy (P = 0.58 by the Wilcoxon rank-sum test).
Overall, 74 (33%) patients reported having missed at least one dose over the four evaluations; there were no significant differences among the randomized groups. In terms of primary endpoint, there was no difference between patients with 100% adherence and those with a lower rate of adherence (P = 0.15). However, adherence and the HIV-1 RNA level at baseline were significant predictors of consistent HIV-1 RNA measurements less than 50 copies/ml. Indeed, 19% of patients with 100% adherence had at least one HIV-1 RNA measurement more than 50 copies/ml compared with 32% in patients with a lower rate of adherence (P = 0.03). All eight patients with an HIV-1 RNA level between 50 and 400 copies/ml at baseline had at least one further HIV-1 RNA level more than 50 copies/ml compared with 20% of the patients with HIV-1 RNA level less than 50 copies/ml at baseline (P < 0.0001). A multivariate model including both adherence and HIV-1 RNA level at baseline could not be estimated due to difficulty in the likelihood estimation. Our data, however, suggest that the two variables were independent predictors of consistent HIV-1 RNA measurements less than 50 copies/ml as there was no association between adherence and HIV-1 RNA level at baseline (from the eight patients with an HIV-1 RNA level between 50 and 400 copies/ml at baseline, four patients had 100% adherence and four patients had a lower rate of adherence).
Resistance to HIV drugs
From the three observed virologic failures, one patient had the V11I mutation at failure, but the mutation was also found retrospectively in a previous sample 7 years prior to study entry. No darunavir resistance-associated mutations were found in the other two patients at failure. No darunavir resistance mutations were also found in the 13 other patients having two consecutive plasma HIV-1 RNA more than 50 copies/ml (11 in the darunavir/r monotherapy group and two in the darunavir/r triple therapy).
Adverse events leading to discontinuation of study drugs occurred in five patients in the triple therapy arm and in four patients in the monotherapy arm (Table 4). There was no difference between arms in grade 3–4 clinical events and laboratory abnormalities. Two patients on darunavir/r monotherapy experienced mild neurological transient symptoms – unusual headaches in a 36-year-old woman and seizures in a 66-year-old man with known untreated epilepsy. Cerebrospinal fluid (CSF) investigation showed no abnormality – neither in cell number nor in protein level – other than a CSF viral load of 330 and 580 copies/ml, respectively, contrasting with a suppressed plasma viremia less than 50 copies/ml. Addition of abacavir and lamivudine to darunavir in the two patients led to improvement in clinical symptoms and decrease in CSF viral load to the lower limit of quantification below 200 copies/ml.
The randomized MONOI study confirmed the high efficacy rate of a darunavir monotherapy strategy in experienced patients with an overall proportion over 85% patients maintaining suppressed viremia at week 48. Results were concordant in the magnitude of difference in efficacy between the two randomized arms in both ITT and per protocol analyses, but conclusions were discordant with respect to the noninferiority margin. Although the difference in efficacy was even lower in the ITT analysis (−4.5%) compared with the per protocol analysis (−4.9%), the former analysis did not demonstrate noninferiority due to a larger CI. Indeed, proportions of treatment success in each arm were lower in the ITT analysis, leading to larger variances, compared with the per protocol analysis. To our knowledge, this is the first time that such discordant conclusions between these two standard analyses occurred in an HIV noninferiority trial. It is admitted that when both analyses lead to the same conclusion, confidence in the trial results is increased . In our study, despite high proportions of patients in treatment success on darunavir/r monotherapy in both ITT and per protocol analyses, we cannot simply conclude to the noninferiority of darunavir/r monotherapy to darunavir/r triple therapy.
Guidance on statistical principles for noninferiority clinical trials indicates that non-ITT analyses might be desirable as a protection from falsely concluding noninferiority from ITT analysis . In general, ITT analysis leads to smaller observed treatment effects than if all patients had fully adhered to both the protocol and the study treatments. Then, in noninferiority trials, ITT analysis will often increase the risk of falsely claiming noninferiority. In our study, although the difference in efficacy was smaller for the ITT analysis compared with the per protocol analysis, the former analysis failed to demonstrate the noninferiority of darunavir/r monotherapy to darunavir/r triple therapy, whereas the per protocol analysis showed noninferiority. Recently, a study with similar treatment groups showed that darunavir/r monotherapy was noninferior to a triple drug regimen including darunavir/r in both ITT and per protocol analyses . One of the main differences between the two studies was the use of a different threshold value to define virologic failure: 50 copies/ml in the MONotherapy in Europe with TMC114 (MONET) trial and 400 copies/ml in the MONOI trial . Recent data suggested that a theshold of 50 copies/ml falsely declared virologic failure for an unacceptably high number of patients who ultimately re-suppress <50 copies/ml without a change in antiretroviral treatment [Poster 580 CROI 2009]. In the AIDS Clinical Trials Group study (ACTG) 5202, virologic failure was defined as a confirmed HIV-1 RNA level of at least 1000 copies/ml at or after 16 weeks and before 24 weeks or at least 200 copies/ml at or after 24 weeks . This may be particularly relevant in the context of strategies using drugs with high genetic barrier to resistance.
Interestingly, the stratified analysis showed that the difference in efficacy between the two treatment groups was larger in patients with a high level of pretherapy HIV-1 RNA. These results indicated that patients, with a known HIV-1 RNA below 100 000 copies/ml before treatment initiation and after achieving a durable period of HIV-1 RNA suppression, might be eligible for darunavir/monotherapy. In addition, the three patients who experienced a virologic failure on darunavir/r monotherapy had no evidence of emergence of new darunavir resistance mutations and re-suppressed after re-introduction of two NRTIs.
A higher proportion of intermittent viremia was seen in the patients randomized to darunavir/r monotherapy (Fig. 2), a feature observed not only in maintenance studies of lopinavir/r monotherapy [8,17], but also in a study on antiretroviral-naive patients . In a large majority of patients, these elevations were transient and subsequent HIV-RNA levels were less than 50 copies/ml without any treatment modification. Prolonged periods of low-level viremia might favor the development of resistance mutations as seen with antiretroviral naive patients on lopinavir/r monotherapy . In our study, no new darunavir resistance mutations were found in the virus of patients experiencing two successive measurements of HIV- 1 RNA more than 50 copies/ml. This is of great importance that preserves future treatment options for patients receiving such a strategy. However, longer follow-up is necessary to consolidate the robustness of the strategy. The cause of these episodes of intermittent viremia is not completely clear, though low adherence has been associated with HIV-1 RNA elevations or virologic failure [28,29]. Adherence to therapy in a context of monotherapy is even more crucial than in triple therapy as suggested in our results in which patients who reported missing doses were more likely to have intermittent viremia.
There are now several randomized studies to suggest that protease inhibitor monotherapy could be a valuable maintenance strategy in virologically suppressed patients. Most of them had involved lopinavir/r and had shown similar efficacy to triple drug therapy [8,17]. As in our study, HIV RNA elevations were mainly transient, in the range of 50–200 copies/ml and did not generally lead to treatment emergent drug resistance.
Because HIV replication has to be optimally controlled, there has been concern that a protease inhibitor monotherapy may not be sufficient in all compartments and reservoirs of HIV. In a study of paired CSF/plasma samples from eight HIV-infected patients, median concentration of darunavir was 34 ng/ml, above the IC50 . In our study, the two patients on darunavir/r monotherapy with discordant CSF plasma HIV RNA had undetectable CSF darunavir concentrations, which might explain the low level HIV replication in the CSF. Furthermore, we recently reported several cases of neurological symptoms and discordant plasma/CSF viral replication in patients receiving standard triple therapy reported as adequate penetrations in CSF . Protease inhibitor monotherapy with darunavir offers an effective alternative strategy for long-term control of HIV infection as considering both ITT and per protocol analyses, 87–94% of patients on darunavir/r monotherapy and 92–99% of patients on darunavir/r triple therapy were on treatment success at week 48. Confidence intervals and noninferiority margin were such that noninferiority could not be demonstrated in both ITT and per protocol analyses. Patients failing darunavir/r monotherapy had no emergence of new darunavir resistance mutations, thus preserving all subsequent therapeutic options, including restarting the previously used NRTIs.
Long-term management of antiretroviral therapy over decades will require different strategies for different patient profiles. We think that protease inhibitor monotherapy, and particularly darunavir monotherapy, has proved itself sufficiently to be progressively introduced in clinical practice. The impact of such strategies on fat distribution and potential other benefits of an NRTI-sparing strategy are under evaluation.
We thank the investigators, study coordinators, site and data managers and the patients for their contributions. We thank Janssen-Cilag for providing darunavir for this trial.
Financial support was received from Agence Nationale de Recherche sur le SIDA et les Hépatites Virales, Paris, France (ANRS-MONOI ANRS 136 trial)).
MONOI ANRS 136 Study group includes the following members: Trial chair: C. Katlama; Trial cochairs: MA. Valantin, C. Duvivier; Trial statistician: P. Flandre; Trial virologist: V. Calvez, AG. Marcelin; Trial pharmacologist: G. Peytavin, AM. Taburet; Scientific Committee: C. Katlama, C. Duvivier, MA. Valantin, V. Calvez, AG. Marcelin, G. Peytavin, S. Kolta, P. Flandre, D. Costagliola, M. Genin, M-J. Commoy, AM. Taburet, M. L'Henaff, A. Cheret; Data Safety and Monitoring Board: F. Raffi, R. Garaffo, D. Descamps, G. Chêne.
Participating centers and investigators (all in France) are as follows:
Hôpital Belfort (Belfort): JP. Faller, P. Eglinger. Hôpital Avicenne (Bobigny): M. Bentata, F. Rouges, F. Touam, A. Boudribila. Hôpital St-Jacques (Besançon): B. Hoen, A. Foltzer. Hôpital Saint Louis (Paris) Medecine Interne: AC. Lascoux-Combes. Hôpital Necker (Paris): C. Duvivier, JP. Viard, O. Lortholary, S. Boucly, A. Maignan. Hôpital Bicêtre (Le Kremlin Bicêtre): J. Ghosn, A. Brunet, M. Môle. Hôpital Raymond Poincaré (Garches): P. De Truchis, H. Berthe. Hôpital Jean Verdier (Bondy): V. Jeantils, S. Tassi. Hôpital Tenon (Paris): L. Slama, E. Chakvetaze, C. Fontaine, L. Iordache. Hôpital A. Béclère (Paris): F. Boue, H. Schoen, D. Bornarel. Hôpital G. Pompidou (Paris): C. Piketty, P. Kousignian. Hôpital Cochin (Paris): D. Salmon, T. Tahi, MP. Pietri. Hôpital Henri-Mondor (Créteil): Y. Levy, C. Dumont. Hôpital Pitié-Salpètrière (Paris) Maladies Infectieuses: C. Katlama, MA. Valantin, H. Ait-Mohand, N. Bentaleb, A. Curjol. Hôpital Pitié-Salpètrière (Paris) Medecine Interne: A. Simon, M. Iguerstira, H. Remidi, M. Bonmarchand, N. Edeb, G. Breton. Hôpital St-Antoine (Paris): PM. Girard, Z. Ouazene, B. Lefebvre, C. Lupin. Hôpital Saint Louis (Paris) Maladies Infectieuses: JM. Molina, D. Ponscarme. Hôpital Zobda-Quitman (Fort De France) A. Cabie, S. Pierre-François, V. Beaujolais. Hôpital St-Andre (Bordeaux): P. Morlat, I. Louis, J. Delaune. Hôtel Dieu (Lyon): C. Trepo, L. Cotte, K. Koffi, B. Lebouche, C. Brochier. Hôpital Ste-Marguerite (Marseille): I. Poizot-Martin, A. Menard, O. Faucher, C. Debreux. Hôpital Bichat (Paris): P. Yeni, N. El-Alami, B. Phung, G. Fraqueiro. Hôpital Gui De Chauliac (Montpellier): J. Reynes, JM. Jacquet, C. Tramoni. Hôpital Archet (Nice): P. Dellamonica, S. Ferrando, A. Leplatois. CHU (Rennes): C. Michelet, C. Arvieux, M. Ratajczak. Hôpital Civil (Strasbourg): JM. Lang, D. Rey, P. Fischer. Hôpital Bretonneau (Tours): P. Choutet, P. Naud. Hôpital Purpan (Toulouse): L. Cuzin, B. Marchou, P. Massip, M. Chauveau, I. Lepain, M. Baronne, F. Balsarin. Hôpital A.Michallon (Grenoble): P. Leclercq, Blanc, S. Gerberon. Hôpital Gustave Dron (Tourcoing): Y. Yasdanpanah, E. Aissi, F. Ajana, M. Valette, S. Pavel, C. Marien, S. Dubus. CHU Nancy-Brabois (Nancy): T. May, S. Wassoumbou. Hôtel Dieu (Paris): E. Aslangul.
C.K. has received travel grant, fees for conference or consultancy fees from Abbott, Bristol-Myers-Squibb, Gilead, GlaxoSmithKline, Jansen-Cilag and MSD. P-M.G. has received grants and/or fees for conferences from BMS, Gilead, GSK, Tibotec and MSD, in the previous 12 months. J-M.M. has received consulting and travel fees from Tibotec, BMS, GSK, Abbott, Gilead, and Merck. G.P. has received travel grants, consultancy fees, honoraria, or study grants from various pharmaceutical companies, including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, Glaxo-Smith- Kline, Janssen Merck and Roche. A-G.M. has received consulting and travel fees from Tibotec, BMS, GSK, Abbott, Gilead and Merck. P.F. has received consulting fees from Janssen-Tibotec, Bristol-Myers Squibb, GlaxoSmithKline, and Abbott; and has received travel sponsorships from GlaxoSmithKline.
Clinical trial registration NCT00421551.
The present study is presented in part in 5th IAS conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 18–22 July 2009 (abstract WELBB102).
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
darunavir; HIV suppressed viremia; maintenance therapy; protease inhibitor monotherapy