JAIDS Journal of Acquired Immune Deficiency Syndromes:
Maraviroc Intensification of Stable Antiviral Therapy in HIV-1–Infected Patients With Poor Immune Restoration: MARIMUNO-ANRS 145 Study
Cuzin, Lise MD*; Trabelsi, Selma PhD†; Delobel, Pierre MD, PhD*,‡; Barbuat, Claudine MD§; Reynes, Jacques MD, PhD‖; Allavena, Clotilde MD¶; Peytavin, Gilles PharmD, PhD#; Ghosn, Jade MD, PhD**; Lascoux-Combe, Caroline MD††; Psomas, Christina MD, PhD‡‡; Corbeau, Pierre MD, PhD‡‡,§§; Flandre, Philippe PhD†; the ANRS 145 MARIMUNO Study group
*Infectious Diseases Department, University Hospital, Toulouse, France
†INSERM U 943 and University Pierre and Marie Curie, UMR-S 943, Paris, France
‡Institut National des Sciences ET de la Recherché Medicale, UMR1043, Toulouse, France
§Infectious Diseases Department, Caremeau Hospital, Nimes, France
‖University Hospital, UMI233, Montpellier, France
¶Infectious Diseases Department, University Hospital, Nantes, France
#Clinical Pharmacy Department, Assistance Publique Hopitaux de Paris, Bichat-Claude Bernard Hospital and EA449 Paris 7 University, Paris
**Department of Internal Medicine and Infectious Diseases, Bicetre University Hospital, Kremlin Bicetre, France
††Infectious Diseases Department, St Louis Hospital, Paris, France
‡‡Immunological Unit, University Hospital Nîmes
§§Human Genetic Institute, CNRS UPR1142, Montpellier University, France.
Correspondence to: Lise Cuzin, MD, Infectious Diseases, Hopital Purpan, Place du Dr Baylac, TSA 40031, 31059 Toulouse Cedex 9, France (e-mail: email@example.com).
L. Cuzin wrote the manuscript and was the principal investigator of the study; S. Trabelsi was the project manager; P. Delobel was in charge of the virological part; C. Barbuat, J. Reynes, C. Allavena, J. Ghosn, and C. Lascoux-Combe were in charge of the study in their clinical centers; G. Peytavin was in charge of the pharmacology; C. Psomas and P. Corbeau were in charge of the immunological part of the discussion; and P. Flandre was in charge of the design and statistical analysis.
Supported by Pfizer and ViiV Healthcare.
Data presented in part as an oral communication in EACS meeting, October, 12–15, 2011, Belgrade (Abstract PS1/6).
The authors have no conflicts of interest to disclose.
Received April 18, 2012
Accepted September 5, 2012
Objective: To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope.
Methods: Patients were eligible if they had CD4 <350 cells/mm3, a CD4 slope <50 cells/mm3 per year, and sustained plasma HIV-RNA <50 copies/mL over the last 2 years, while receiving a stable cART. Patients harboring pure X4-using viruses by a phenotypic tropism assay were excluded. MVC was added to cART for 24 weeks, at the recommended dosage per drug–drug interactions. The primary endpoint was a significant positive difference in CD4 slopes (with MVC— pre-MVC, paired t test).
Results: Sixty patients (55 men), with median age 51 years, baseline CD4 238 cells/mm3, and slope before intensification +14.1 cells/mm3 per year were included. CD4 nadir was <50/mm3 in 47% of the population. The full set of patients (N = 57) completed week 24, and the on-treatment patients (N = 48) did not discontinue MVC. The median CD4 slope difference from baseline was +22.6 cells/mm3 per year (P = 0.08) in full set and +22.6 cells/mm3 per year (P = 0.04) in on-treatment. Slope evolution was not different according to baseline tropism, CD4 nadir, or ongoing cART regimen. No drug-related severe adverse events were recorded during intensification. MVC plasma concentrations were significantly different depending on drug–drug interaction with ongoing cART regimen and tended to be correlated with CD4 cells increase.
Conclusion: In this study, MVC intensification of stable cART over 24 weeks was able to enhance CD4 cell slopes in patients with prior insufficient immune restoration despite long-term virological control.
Even in patients experiencing virological control under potent combined antiretroviral therapy (cART), CD4 cell count restoration of more than 500 cells/mm3 is obtained in roughly 50% of the patients.1,2 This incomplete immune restoration has been linked with higher morbidity and mortality.2–6 The reasons for this incomplete restoration include persistent viral replication, ongoing immunoactivation, or other causes.7,8 To date therapeutic intensification strategies including immunomodulating or antiretroviral drugs provided discordant results in this setting.9–12
Maraviroc (MVC) belongs to a class of antiretroviral drugs, the activity of which is based on the CCR5 cell receptors blockade. Even if some questions are still under debate about long-term toxicity of CCR5 blockade,13 the drug has not been related with short-term severe adverse events in clinical trials.14–16 In the main pilot studies, evaluating MVC efficacy in immunorestoration of antiretroviral naive16 or experienced patients15 was better in the MVC receiving groups than in the control groups, even in the absence of virological success.17 A meta-analysis of all recently launched antiretroviral drugs showed greater immunological efficacy of anti-CCR5 drugs versus protease inhibitors,18 even if this has not been confirmed in some populations.19 The rationale for this observed CD4 cell restoration could be based on the immunological properties of the drug,20 or on reducing a possible persistent viral replication in anatomical sanctuaries.21 The MVC pharmacological properties regarding penetration in anatomical compartments, such as liposolubility, molecular mass, protein binding, and efflux transporters substrate,22–24 could be important in reaching these goals.
The aim of our prospective multicenter noncomparative pilot study was to investigate the ability of intensification of a stable and efficient cART by a 24-week MVC course to significantly increase the CD4 cell count slope. We also planned to analyze exhaustively the underlying immunological and virological mechanisms in this small but well-described population.
Eligible patients were HIV-infected adults receiving a well-tolerated cART with no treatment modification in the last 6 months, who had achieved virological suppression, with all plasma HIV1-RNA measurements less than 50 copies/mL over the last 2 years, and with insufficient immunological restoration. Insufficient immunological restoration was defined as having all CD4 cell count measurements less than 350 cells/mm3 with a regression slope of less than +50 cells/mm3 per year during the last 2 years. Patients had to be MVC naive and were required to have blood cells and serum chemistry values within acceptable ranges. Major noninclusion criteria were pregnancy (ongoing or intended), breast feeding, previous treatment with any immunomodulating drugs (including interferon), or current tuberculosis or hematological disease likely to be responsible for low CD4 cell count by themselves.
The TTT phenotypic entry assay was used to determine viral tropism from HIV-1 DNA in the PBMCs.25 Tropism determination was performed 12 weeks before and on the first day of treatment intensification. Patients with pure X4 using viruses were excluded. As a partial activity of MVC against the R5 side of R5X4 viruses was expected, we decided to keep patients with R5 or DM viruses in the study. But more than its virological effect, the hypothesis was that if MVC had an immunological activity, it would be independent of the viral tropism. With the aim of reducing the frequency of premature treatment interruptions, the results of phenotypic assays other than pure X4 were not communicated to the investigator.
The study was a multicenter, noncomparative, prospective 36-week trial conducted in 16 “Agence nationale de recherche sur le sida et les hépatites” (ANRS) sites in France. The ethics committee in Toulouse, France approved the protocol (EudraCT: 2009-011171-76). All patients gave written informed consent. MVC was added to the stable preexisting cART following European recommendations according to the predictable drug–drug interactions, that is, 150 mg twice daily with ritonavir-boosted protease inhibitors (bPIs) (except for boosted tipranavir or fosamprenavir), 600 mg twice daily with efavirenz or etravirine, or 300 mg twice daily in other situations.26
Patients were assessed 12 weeks before treatment intensification, at day 0, and then at weeks 4, 12, and 24 during intensification. Postintensification monitoring was done at weeks 28 and 36. At each visit, clinical data were collected through an interim medical history and physical examination, and blood specimens were drawn. Routine analyses were performed at each visit and included a complete blood count, CD4 cell count, plasma HIV-RNA levels, and tests for liver and kidney functions. MVC plasma concentration was assessed at weeks 4, 12, and 24. All immunological and virological laboratories of ANRS sites had participated previously in quality-control programs, so CD4 cell counts and viral load measurements were assessed locally in each site. MVC plasma concentrations were measured in the Bichat Claude Bernard Unit using a validated liquid chromatography coupled with tandem mass spectrometry method (Acquity UPLC—Acquity TQD) after sample extraction (level of quantification < 1 ng/mL), at any time after the last drug intake (MVC Call), as previously described.27 MVC plasma protein binding (total and free fractions) was performed in duplicate using an ultrafiltration assay with Centrifree devices. MVC Call was interpreted according to the threshold of 75 ng/mL (target plasma concentration for virological efficacy).28 Safety was assessed by reporting all adverse events and laboratory abnormalities, the severity of which were assessed using of the ANRS toxicity grading scale.29
Quantification of HIV-1 DNA Load in the PBMCs
Total HIV-1 DNA was quantified by real-time quantitative polymerase chain reaction using a Taqman probe on a LightCycler 480 (Roche). Quantification of the beta-globin gene was performed in parallel to assess the number of cells in the sample.
Quantification of residual HIV-1 RNA Viremia
Plasma HIV-1 RNA less than 50 copies/mL was quantified using an ultrasensitive quantitative real-time reverse transcriptase–polymerase chain reaction assay on a LightCycler 480 (Roche) with a limit of detection of one copy per milliliter (adapted from Ref. 30).
CD4 and CD8 Cells Activation
Cells in 50 μL of blood were labeled with saturating concentrations of PerCP/Cy5.5-conjugated anti-CD3 monoclonal antibody (mAb), APC-conjugated anti-CD4 mAb, APC/H7-conjugated anti-CD8 mAb, PC7-conjugated anti-HLA-DR mAb, and FITC-conjugated anti-CD38 mAb (all mAb from Becton-Dickinson, San Jose, CA). Thereafter, red blood cells were lysed and white blood cells analyzed by flow cytometry.
The primary endpoint was the difference between CD4 cell slopes while taking MVC by comparison with preintensification. Secondary end points included durability, efficacy, safety, and pharmacology measurements. Durability was assessed by CD4 cell counts evolution between weeks 24 and 36. Efficacy was assessed by the proportion of patients with a CD4 cell count increase of more than 50 or 100 cells/mm3 between day 0 and week 24, and by HIV-1 DNA and ultra sensitive plasma HIV-RNA evolutions during intensification. Safety was assessed by the proportion of patients with plasma HIV-RNA remaining less than 50 copies/mL at weeks 4, 12, and 24, the proportion of patients with appearance of new resistance-related genotypic mutations or with tropism evolution during intensification, the number of clinical events (HIV related or not), and the frequency and reasons for treatment modification. MVC Call was evaluated at day 0, weeks 12 and 24, and a correlation with CD4 cell count evolution was estimated using the week 24 values.
ANRS 145 was a single-arm pilot study with a paired difference in CD4 cell count slopes (CD4 slope under MVC intensification minus CD4 slope before MVC intensification) as the primary endpoint. The preintensification slope was based on at least 3 CD4 cell measurements per year for the last 2 years before entry in the study. The CD4 slope under MVC intensification was based on CD4 cell counts at day 0, weeks 4, 12, and 24. Hypothesizing an average gain in CD4 before intensification of 25 cells per year and an average gain of 50 cells per year under MVC intensification, 60 patients were enrolled to provide a power of 77% assuming a standard deviation of the difference of 70 and 2-sided test with a 0.05 significance level. The Anderson–Darling test for normality of the difference in CD4 slopes was planned to choose either a paired t test (no rejection of the normality hypothesis) or a signed rank test (rejection of the normality hypothesis). Between groups, comparisons were carried out by the Kruskal–Wallis test for continuous variables and by the Fisher exact test for categorical variables.
Between September 2009 and February 2010, 88 patients underwent screening procedure and 61 were eligible, but one could not participate because of recent incarceration. From the 60 patients, 3 withdrew consent before week 24 for personal reasons; the full set (FS) of patients to evaluate the primary endpoint is thus based on 57 patients. Among them 48 did not discontinue MVC, constituting the on-treatment (OT) set. The 9 cases of MVC discontinuation were personal reasons in 5, mild or benign adverse events in 3, and a non-MVC related severe adverse event in one.
The baseline characteristics of the total population (n = 60) are shown in Table 1. Preintensification regimen was a triple cART based on a bPI without nonnucleosidic reverse transcriptase inhibitor (NNRTI) in 62% and with an NNRTI in 8% of patients, on an NNRTI without bPI in 27% of patients, and on other strategies—mainly multiple drug regimens—in 3% of patients. In patients with dual/mixed (D/M) viruses, the median CD4 cells nadir was lower than in patients with R5 viruses [respectively, 34 (11–73) and 73 (49–100), P = 0.02]. In the 60 patients included, the median preintensification slope was of +14.1 (−7.4; +27.2) CD4 cells/mm3 per year and was significantly different between patients with R5 using viruses [−1.03 (−15; +21)] and those with D/M viruses [+21.9 (1.4; +32.2), P = 0.008]. Treatment intensification consisted of MVC 150 mg twice daily in 41 (68%), 600 mg twice daily in 12 (20%), and 300 mg twice daily in 7 (12%) of the patients.
The CD4 cell slopes before, during intensification, and their differences are summarized in Table 2 for both the FS and OT populations. The median CD4 cell count slope during MVC intensification was +27.3 (−20; +92) cells per year for the FS population and +30.2 (−13; +96) cells per year for the OT population. The median differences between the 2 CD4 cell slopes (slope under MVC intensification minus slope before MVC intensification) were similar for both the FS and OT populations. The difference indicated a trend toward statistical significance in the full set population (t test, P = 0.084) and was significant in the OT population (P = 0.04). Slopes for each patient enrolled in the study are displayed (Fig. 1) by slopes before and during inclusion in the ANRS 145 study. Twenty patients had a negative CD4 cell slope during MVC intensification, 7 of whom also had a negative pre-MVC CD4 cell slope. Twelve patients had a CD4 cell slope >100 CD4 cells per year during intensification (max 383 CD4 cells per year), 3 of whom had a negative pre- MVC CD4 cell slope. Differences in slopes did not vary according to baseline viral tropism, CD4 cell nadir, type of antiretroviral regimen before intensification, nor MVC prescribed dosage.
The median differences in absolute CD4 cell counts between day 0 and week 24 were +19 cells/mm3 (−10; +41) and +22 (−4; +44) in the FS and OT populations, respectively. Between week 24 and week 36, they were of −11 cells/mm3 (−44; +27) and −12 (−50; +18) in the FS and OT populations, respectively. Increases in CD4 cell count of more than 50 cells/mm3 and 100 cells/mm3 between day 0 and week 24, respectively, were observed in 21% and 3.5% of the FS population and in 23% and 4.0% of the OT population, respectively. Median change in CD4 cell counts between week 24 and week 36 were −11 (−44; 27) and −12 (−50; +18) in the FS and OT population, respectively. The proportions of CD4 cells among CD3 lymphocytes did not vary during intensification.
Total HIV DNA quantification at day 0 was 2.4 log·copies per 106 PBMCs and was not significantly altered during the intensification (2.31 and 2.47 log·copies per 106 PBMCs at weeks 12 and 24, respectively) nor after MVC discontinuation (2.43 log·copies per 106 PBMCs at week 36). Ultra sensitive plasma HIV-RNA viremia was detectable in 54% of the patients at baseline, with a median of 2.14 copies/mL. The level of the residual viremia did not change during intensification. Viral blips were observed in 6 patients at one time during the study, in all cases, plasma HIV-RNA was found to be <50 copies/mL at the next visit.
Among the 28 patients with pure R5 viruses at baseline, one was found to harbor D/M population at week 24, reverting to pure R5 at week 36. Among the 32 patients with D/M viruses at baseline, we did not find any significant change in tropism during the study.
Severe clinical events occurring during MVC intensification were described in 5 patients accounting for 7 events. Most of them were not considered to be related with MVC: car accident, digestive hemorrhage and anemia, lumbago, prostatic inflammation, acute febrile diarrhea, and faintness during phlebotomy. For the patient who fainted during phlebotomy at week 4, we proposed study—and MVC—discontinuation as to avoid further accidents. MVC trough plasma concentration at this visit in this patient was below quantification, ruling out any MVC direct effect. One patient presented with an acute cervical adenitis because of Mycobacterium tuberculosis between weeks 4 and 12, and then developed rifampicin-induced hepatitis between weeks 12 and 24. Unmasked tuberculosis could not be ruled out, even if the patient was already receiving an effective cART regimen for at least 2 years before MVC intensification and did not have any history of tuberculosis diagnosis. Mild or benign events led to treatment discontinuation in 3 cases and finally, 5 patients decided not to pursue for personal reasons (change in care provider or difficulties to comply with the protocol schedule).
No antiretroviral modification, neither in drug nor in dosage, was required during MVC intensification. Pharmacology assessment results only in the OT population are shown in Table 3. Median interval between last drug intake and sampling for MVC Call was 13.17 hours (interquartile range, 11.5–14.17). Total and free MVC plasma Call were very similar at weeks 12 and 24, between 300 and 600 mg twice daily dosages, but significantly lower than in patients receiving 150 mg twice daily with PI/r-containing regimen. The percentage of MVC unbound fraction to plasma protein of MVC Call was relatively stable (approximately 40%) across the MVC doses and regimens. Overall, 63%, 49%, and 63% of patients had total MVC Call more than 75 ng/mL at weeks 4, 12, and 24, respectively. A tendency was observed toward a correlation between MVC plasma Call and the CD4 increase at week 24 (r = 0.13, P = 0.099).
The immunological substudy was performed on a subpopulation of 31 patients. The results are shown in Figure 2. Changes in the proportions of CD4 DR+ were not significant either during or after intensification. Proportions of CD8+DR+, CD8+CD38+, and CD8+DR+CD38+ significantly decreased during intensification and increased after intensification.
In this prospective, multicenter, noncomparative pilot study investigating the ability of a 24-week MVC course intensification of a stable and efficient cART to significantly increase the CD4 cell count slope, we found positive results in patients who took the drug during 24 weeks. In this population, per intensification CD4 cell slope was around twice the preintensification slope (+30 CD4 cells/mm3 per year vs. +15 cells/mm3 per year), and a median loss of 12 cells/mm3 was observed during the 12 weeks after MVC discontinuation. This positive effect was not related with any baseline characteristic that we were able to investigate and was not different between patients harboring pure R5 or D/M using viruses at baseline. The decrease after intensification, previously observed in ACTG 5256 in the same conditions,31 may be in favor of a positive effect of intensification. Neither ultrasensitive quantification of plasma HIV-RNA nor HIV-1 DNA was altered by treatment intensification. These results are in agreement with previous studies of cART intensification that have similarly shown a stability of these markers.10,32,33 However, it does not preclude the possibility that low-level residual virus replication persists in lymphoid tissues despite cART. Intensification with MVC was virologically and clinically safe. Nevertheless, in one patient, the immunomodulation might have unmasked a mycobacterial infection. Some patients had viral blips during the study, but the frequency of these events was not different from what has been described by others.34
MVC concentrations sufficient for a virologic effect (>75 ng/mL) were reached in most patients receiving MVC, in addition to a ritonavir bPI regimen; whereas, they were significantly lower in patients receiving MVC, in addition to an NNRTI regimen—despite dosage adjustments according to recommendations. The boosting effect of ritonavir may apply on MVC and on PIs, allowing reduced dosing and intake frequency.35 Yet in all patients, MVC concentrations remained more than 10 ng/mL, a concentration supposed to saturate all the membrane CCR5 molecules.36 MVC concentrations might need to be higher to block the immunologic functions of CCR5.37,38 Thus, we cannot exclude that in our study, insufficient dosing might be a cause of nonimmunologic response to MVC in some patients and that the observed tendency toward a correlation between total MVC concentration and the CD4 increase at week 24 may have been hampered in the patients in whom the dosing did not reach adequate concentrations. MVC Therapeutic Drug Monitoring (using free MVC plasma concentrations if possible) might be recommended in such strategy, especially with enzymatic inducers containing regimens (as NNRTI) without ritonavir boosting.
CCR5 antagonists may modify CD4 cell counts by various mechanisms. The effect might be the consequence of the inhibition of the chemotactic function of CCR5, resulting in the redistribution of the T cells. Yet, such a phenomenon has not been observed in healthy controls. Alternatively, the drug could modulate the role played by CCR5 in immune activation.20 Even if the immunological results we present here are incomplete, the same results have been described by Wilkin et al.31 As immune activation is a main cause of nonimmune response to cART, blocking this function might boost CD4 restoration. In addition, as CCR5 has also been involved in apoptosis,20 CCR5 antagonism might reduce programmed cell death, a major cause for loss of CD4 cells. Previous studies have tested the effect of MVC intensification on the CD4 restoration of nonimmunologic responders. Some of them showed an increase in CD4 cell counts,39,40 whereas others did not.12,31,41,42 Our results are in keeping with another MVC intensification study, which had the same design on a similar population.31 On the opposite, the only MVC intensification study with a placebo controlled design42 did not show any immunological benefit. Neither pharmacological data nor the preintensification regimens were provided when the results of this study were presented. Other explications for the discrepancies observed between studies could be the causes of the nonimmunologic responses to cART. These causes may vary from one patient to another7 and some of them could be sensitive to CCR5 blocking and others not. One of these factors could be the clinical stage of the patient or the level of immune activation. This might explain the discrepancy between our data and those of Hunt et al.42 Finally, genetic factors apart from the CCR5 axis might modulate the role played by CCR5.43
Our study has some limits. First, some therapeutic strategies have been shown to be able to enhance CD4 cell counts with no associated clinical benefits for the patients.9 The clinical relevance of the statistically significant increase in CD4 cell count slopes is questionable. Nevertheless, intensification duration was short, and the slopes did not seem to reach a plateau effect. Moreover, data collected after MVC discontinuation, in our study and in the ACTG 5256,31 showed that modifications observed during intensification tended to return to baseline after MVC discontinuation. One can speculate that a longer duration of MVC intensification would have yielded to a clinically significant CD4 cell count increase. As long as MVC does not lead to severe adverse events15,16 and low CD4 cell count remains the major cause of HIV-related and non–related morbidity and mortality,2–6 it could be worth pursuing investigations in this field. We did not have any control group in this study, but the design allowed each patient to act as its own control.
In conclusion, we found that a short course of MVC intensification was safe and could lead to a moderate but significant CD4 cell count slope modification. Further studies on larger populations are needed to fully assess the clinical relevance of these findings.
ANRS 145 MARIMUNO study group: L. Cuzin (principal investigator), S. Trabelsi (project management), P. Flandre (trial methodologist and statistician), P. Delobel (virology coordination), B. Autran (immunology coordination), P. Corbeau (immunology coordination), G. Peytavin (pharamcology coordination), C. Lascoux-Combes (associated clinical investigator), J. Ghosn (associated clinical investigator), J. Reynes (associated clinical investigator), C. Lemarchand (ViiV Healthcare, France), S. Couffin-Cadiergues, and M. J. Commoy (ANRS clinical research team).
Participating centers and investigators: Nîmes (C. Barbuat), Montpellier (J. Reynes), Nantes (F. Raffi and C. Allavena), Marseille (I. Poizot-Martin), Paris Pitié Salpètrière (C. Katlama), Toulouse (L. Cuzin, M. Chauveau, and D. Garipuy), Paris Necker (C. Duvivier), Paris HEGP (C. Piketty), Tourcoing (Y. Yazdanpanah), Paris St Louis Infectious Diseases (J. M. Molina), Paris St Louis Internal Medicine (C. Lascoux-Combe), Besançon Dermatology (C. Drobacheff-Thibault), Besançon Infectious Diseases (B. Hoen), Kremlin Bicêtre (C. Goujard), Créteil (Y. Lévy), and Nice (J. Durant).
The authors thank A. Baakili and C. Lemarchand and Pfizer and ViiV Healthcare Laboratories for graciously providing maraviroc and continuous support. This research was conducted with the support of Pfizer.
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