The advent of combination antiretroviral therapy has significantly reduced the morbidity and mortality of HIV-1.1 Current treatment guidelines recommend the use of 2 nucleoside reverse transcriptase inhibitors (NRTIs) to form a “backbone,” which is combined with a third agent from a different antiretroviral drug class.2 However, despite the distinct benefits of NRTI-based therapies, toxicity can be a limiting factor. Adverse effects of the NRTI class include mitochondrial toxicities, such as pancreatitis, cardiomyopathy, peripheral neuropathy, hepatic steatosis, and lipoatrophy.3 Drug-specific adverse effects include rash and hypersensitivity reactions (abacavir), nephrotoxicity and bone toxicity [tenofovir (TDF)], and bone marrow suppression and lipoatrophy (zidovudine).4,5
Maraviroc (MVC) is a potent selective CCR5 antagonist approved for the treatment of HIV-1 in treatment-naive and treatment-experienced patients in the United States6 and treatment-experienced patients in the European Union.7 MVC is an attractive option for treatment-naive patients due to its increasing record of safe use8,9; furthermore, the benefits of MVC treatment are more likely obtained in previously untreated patients at a relatively early stage of infection as HIV-1 that exclusively uses the CCR5 coreceptor predominates early in the course of infection,10,11 whereas HIV-1 that exclusively uses the CXCR4 coreceptor has been found in <1% of treatment-naive patients.10,11
Efficacy and pharmacokinetic (PK) data from previous studies demonstrated the potency of MVC when given as a 300 mg, equivalent once-daily dose.12–17 Given the high medical need to simplify dose regimens and enhance adherence, the primary objective of this study was to evaluate the efficacy and safety of a dual-therapy, nucleoside-sparing once-daily regimen of MVC 150 mg and ritonavir-boosted atazanavir (ATV/r; 300/100 mg) in treatment-naive patients with CCR5-tropic HIV-1. This dose with protease inhibitors (PIs), including ATV/r, has proved efficacious and well tolerated in treatment-experienced patients.14,15 Secondary objectives included safety and tolerability, virological and immunological responses over time, and evolution of viral resistance and/or tropism in patients who fail treatment.
Study A4001078 is an open-label, randomized, 2-arm, international phase 2b study, conducted at 33 centers in Germany, Spain, and the United States. The study was designed with a 48-week treatment period, which was later extended to 96 weeks. The study was registered with clinicaltrials.gov (NCT00827112) and was conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed. The study protocol was approved by institutional review boards or independent ethics committees at all study centers, and patients provided written informed consent. An independent Data Monitoring Committee was responsible for ongoing monitoring of the efficacy and safety of patients in the study.
Patients were enrolled by investigators and were randomized according to a computer-generated pseudorandom code using the method of permuted blocks. Randomization numbers were assigned by a central web/telephone randomization system, and study medication was dispensed by assigning the appropriate container numbers to patients based on their assigned treatment groups. As this was an open-label study, there were no blinding requirements.
Eligible patients were aged ≥16 years, treatment-naive, and had only R5 HIV-1 at screening using the Trofile assay with enhanced sensitivity (Monogram Biosciences, San Francisco, CA). Further eligibility criteria included plasma HIV-1 RNA ≥1000 copies per milliliter and CD4 cell count ≥100 cells per cubic millimeter at screening. Patients were excluded if they: had a suspected or documented active, untreated HIV-1–related opportunistic infection or any other condition requiring acute therapy; had received previous antiretroviral therapy for >14 days at any time; or had evidence of resistance to ATV, TDF, or emtricitabine (FTC) (by GenoSeq and/or PhenoSenseGT; Monogram Biosciences).
Patients were randomized 1:1 to receive MVC 150 mg once daily + ATV/r 300/100 mg once-daily or TDF/FTC 300/200 mg once daily + ATV/r 300/100 mg once daily. All medications were tablets for oral administration. MVC could be taken with or without food; missed doses could be taken unless it was <6 hours before the next planned dose. ATV/r and TDF/FTC were taken according to the package inserts. Plasma ATV/r exposure is enhanced by food18; therefore, MVC + ATV/r was taken with food to optimize the extent of the boosting effect on MVC. Patients experiencing symptomatic unconjugated hyperbilirubinemia attributable only to ATV/r, who were responding to the therapy without evidence of virological failure, and who wished to discontinue ATV were permitted to switch to either darunavir/ritonavir (DRV/r; 800/100 mg) once daily or lopinavir/ritonavir (LPV/r; 400/100 mg) twice a day per protocol and remain in the study; switching could only take place on a single occasion at any point in the study. Patient adherence to treatment was evaluated based on tablet/capsule counts at each study visit and information, such as plasma HIV-1 RNA levels.
After initiation of treatment (baseline), study visits and sample collection were scheduled at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, and 96. Samples for PK analysis [MVC AUC24, minimum concentration (Cmin), maximum concentration (Cmax), Cavg, and time to maximum concentration (Tmax)] were taken from the first 15 patients enrolled in the United States on days 4, 7, 10, and at the week 2 visit immediately predose, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose. Sparse PK samples with dosing information were collected at the week 2, 12, and 24 visits.
Blood samples (5 mL) to provide a minimum of 2 milliliters plasma for analysis of MVC were collected into tubes containing sodium heparin. Blood samples were centrifuged, and plasma was stored at approximately −20°C within 1 hour of collection. Samples were assayed for MVC using solid-phase extraction and a validated high-performance liquid chromatography/dual mass spectrometry assay.
The primary endpoint was the proportion (%) of patients with plasma HIV-1 RNA <50 copies per milliliter at week 48 (missing, discontinued = failure). HIV-1 RNA levels were determined using the real-time polymerase chain reaction (Roche Amplicor v1.5, Roche Molecular Diagnostics, Pleasanton, CA) assay. Secondary endpoints included: the percentage of patients who achieved plasma HIV-1 RNA <50 copies per milliliter and <400 copies per milliliter at each postbaseline visit, and changes in CD4 and CD8 cell counts (assessed by flow cytometry) from baseline at weeks 16, 24, and 48. Samples for genotypic and phenotypic resistance analyses (GenoSeq and/or PhenoSenseGT assays; Monogram Biosciences) and for determination of HIV coreceptor tropism (Trofile assay; Monogram Biosciences) were collected from patients who discontinued early due to protocol-defined treatment failure or who had plasma HIV-1 RNA ≥500 copies per milliliter at week 48.
Protocol-defined treatment failure was defined as: <1.0 log10 copies per milliliter decrease from baseline in plasma HIV-1 RNA at week 4 or thereafter; failure to achieve plasma HIV-1 RNA <400 copies per milliliter at week 24; or an increase in plasma HIV-1 RNA to detectable levels (≥1000 copies/mL on 2 consecutive measurements ≤ 14 days apart) in patients previously confirmed to have undetectable levels of <400 copies per milliliter on 2 consecutive visits. Any patient who experienced protocol-defined treatment failure was discontinued from the study.
Safety and tolerability endpoints included the incidence of treatment-emergent adverse events (AEs), AEs leading to discontinuation, serious AEs (SAEs), and laboratory test abnormalities.
In an amendment on December 22, 2008, a positive result for hepatitis B surface antigen was added to the exclusion criteria because TDF/FTC, but not MVC, can be used for the treatment of hepatitis B and could bias study results. A further amendment on June 3, 2009 permitted patients who had grade 3 or 4 hyperbilirubinemia without elevations of transaminases (attributed to ATV/r) and without protocol-defined treatment failure to switch to DRV/r or LPV/r. This amendment altered the HIV-1 RNA cut-off for the definition of protocol-defined treatment failure at week 24 from <50 to 400 copies per milliliter. This was changed because patients who started with very high RNA levels could have taken longer than 24 weeks to achieve <50 copies per milliliter and may have been discontinued prematurely.
As this was a phase 2b exploratory study, it was not powered to show a difference between the treatment arms. Therefore, sample size was determined based on feasibility, and findings would be used to inform the design of a future phase 3 study if warranted. It was anticipated that approximately 80 patients would provide adequate data to enable calculation of the point estimate and 95% confidence interval (CI) for each treatment group with reasonable precision. Virology analyses were performed on the Full Analysis Set population, which comprised all patients who received ≥1 dose of study treatment and had a baseline and ≥1 postbaseline measurement. Continuous measurements were summarized using descriptive statistics and frequency counts. No formal statistical testing was performed. If a patient discontinued from the study, they were treated as failures or nonresponders in the primary endpoint analysis at that visit and all visits thereafter. Interim analyses were performed after the initial 15 patients enrolled per treatment group had completed 2 weeks and after all patients had completed 24 weeks.
A total of 220 patients were screened and, of these, 121 received ≥1 dose of study treatment (Fig. 1). The majority of screen failures were due to dual/mixed tropism (n = 38) or nonreportable tropism (n = 18). All patients who received treatment were analyzed for drug safety, and 120 patients were analyzed for virological outcomes (1 patient in the MVC group was lost to follow-up without a postbaseline plasma HIV-1 RNA assessment). At week 48, 7 patients had discontinued in each arm (Fig. 1), and 2 patients in each arm experienced protocol-defined treatment failure. There were no deaths reported up to the 48-week cut-off point.
Demographic and baseline clinical characteristics were similar in both treatment arms (Table 1). Patients in the MVC group had a longer mean duration since diagnosis and a slightly lower CD4 cell count at baseline compared with patients in the TDF/FTC group. Both groups were well balanced in terms of plasma HIV-1 RNA at baseline.
Ten patients (7 in the MVC group and 3 in the TDF/FTC group) switched from ATV/r due to symptomatic unconjugated hyperbilirubinemia (either jaundice, sclera icterus, or both); 8 patients switched to DRV/r in the MVC group and 2 in the TDF/FTC group; and 2 patients switched to receive LPV/r instead of ATV/r (1 patient in each group).
At week 48, 44/53 (74.6%; 95% CI: 63.5% to 85.7%) and 51/54 (83.6%; 95% CI: 74.3% to 92.9%) patients in the MVC and TDF/FTC treatment groups, respectively, achieved plasma HIV-1 RNA <50 copies per milliliter. The proportions of patients with plasma HIV-1 RNA <50 copies per milliliter at week 48 in both treatment groups were similar to those observed from week 16 onward (Fig. 2A). The proportions of patients with plasma HIV-1 RNA <50 copies per milliliter at week 24 and week 48 stratified according to baseline viral loads are shown in Figure 2B.
Nine patients in the MVC group and 3 patients in the TDF/FTC group were not considered treatment failures but had low-level viremia (plasma HIV-1 RNA >50 copies/mL) at week 48. Before week 48, all these patients had previously suppressed plasma HIV-1 RNA to <50 copies per milliliter; 2 patients subsequently failed to resuppress to <50 copies per milliliter HIV-1 RNA (see Table S1, Supplemental Digital Content 1, http://links.lww.com/QAI/A367).
The 10 patients who switched from ATV/r to either DRV/r or LPV/r achieved plasma HIV-1 RNA <50 copies per milliliter before switching and remained suppressed (plasma HIV-1 RNA <50 copies/mL) at week 48.
The proportions of patients with plasma HIV-1 RNA <400 copies per milliliter were similar from week 16 onward in each treatment group (see Figure S1, Supplemental Digital Content 1, http://links.lww.com/QAI/A367). At weeks 16, 24, and 48, there were 52/54 (88.1%), 54/56 (91.5%), and 53/53 (89.8%) patients, respectively, in the MVC group and 56/58 (91.8%), 57/58 (93.4%), and 53/54 (86.9%) patients, respectively, in the TDF/FTC group with plasma HIV-1 RNA <400 copies per milliliter.
Using the last observation carried forward approach, median (range) change from baseline in CD4 cell count at week 48 was +173 (−142 to 609) and +187 (−100 to 585) cells per cubic millimeter with MVC and TDF/FTC, respectively (Fig. 2C).
Three patients in each treatment group had discontinued treatment early with sufficient plasma HIV-1 RNA at week 48 for virology analysis (≥500 copies/mL) [MVC: AE (n = 1; week 12), lost to follow-up (n = 1; week 32), protocol-defined treatment failure (n = 1; week 24); TDF/FTC: lost to follow-up (n = 2; week 12), protocol violation (n = 1; week 32)]. No resistance to any component of either treatment regimen was observed in virus from these patients, and no change in viral tropism or susceptibility to MVC was observed with virus from MVC recipients.
Treatment-emergent (treatment-related) AEs of any severity grade were reported by 96.7% (58/60) [68.3% (41/61)] of patients receiving MVC and 98.4% (60/61) [67.2% (41/61)] of patients receiving TDF/FTC. There were 2 discontinuations due to AEs, vomiting, and jaundice (both classified as moderate); both were in the MVC treatment group and both were considered treatment-related. Treatment-emergent AEs occurring in ≥10% patients in either treatment group are shown in Supplemental Digital Content 2 (see Table S2, http://links.lww.com/QAI/A367). The most frequently reported AEs in each group were: MVC, AEs potentially related to hyperbilirubinemia and diarrhea; TDF/FTC, AEs potentially related to hyperbilirubinemia, nausea, and diarrhea. Grade 3/4 AEs were reported by 29/60 (48.3%) and 18/61 (29.5%) patients in the MVC and TDF/FTC groups, respectively. The majority of these were hyperbilirubinemia, and in all but 1 case, this was due to increases in unconjugated bilirubin that were not associated with transaminase increases. Twenty-two patients experienced SAEs, 10/60 (16.7%) in the MVC group and 12/61 (19.7%) in the TDF/FTC group. One patient [1.7% (1/59)] in the MVC treatment group experienced an SAE of nephrolithiasis, which was attributed to ATV; none of the other SAEs were attributed to study treatment by investigators.
The majority of patients in both treatment groups [MVC, 57/59 (96.6%); TDF/FTC, 56/61 (91.8%)] had laboratory test abnormalities following a normal baseline, the majority of which were hyperbilirubinemia (see Table S2, Supplemental Digital Content 2, http://links.lww.com/QAI/A367). There were no lipid abnormalities recorded in patients with normal lipids at baseline. Change from baseline in mean (SD) creatinine clearance, calculated using the Cockcroft–Gault formula, was greater in the TDF/FTC group compared with the MVC group at all time points (see Figure S2, Supplemental Digital Content 2, http://links.lww.com/QAI/A367).
Analysis of PK parameters in the first 15 patients enrolled in the United States showed that following multiple-dose administration of MVC 150 mg once daily, median (range) AUC24 was 4330 (1930–7310) ng.h per milliliter; Cavg was 180 (80.3–305) ng per milliliter; Cmax was 650 (178–1490) ng per milliliter; Cmin was 37.0 (8.44–92.7) ng per milliliter; and Tmax was 2.00 (0.50–3.92) hours. There were 139 sparse PK samples with dose and time of dose data recorded, yielding MVC concentrations from 13.7 to 933 ng/mL with samples collected from 0 to 32 hours postdose. For all patients, including those participating in the PK substudy, all plasma concentrations remained above the in vivo half maximal inhibitory concentration (7.65 ng/mL)19 at all time points.
This open-label study in treatment-naive patients with CCR5-tropic virus showed that a high proportion of patients in the MVC and TDF/FTC treatment groups achieved and maintained viral suppression through 48 weeks of treatment. When stratified by plasma HIV-1 RNA concentration at baseline, the number of patients who achieved a response (plasma HIV-1 RNA <50 copies/mL) at week 48 was higher in the TDF/FTC treatment arm compared with the MVC group. CD4 cell counts increased from baseline in both treatment groups. At week 48, 1 patient in the MVC arm had a low CD4 cell count (due to chemotherapy), which subsequently recovered. It is noteworthy that, at week 48, the majority of patients who did not achieve a full response had plasma HIV-1 RNA <400 copies per milliliter. Seven of 9 patients in the MVC group who had plasma HIV-1 RNA ≥50 copies per milliliter at week 48 subsequently resuppressed to <50 copies per milliliter HIV-1 RNA, and the week 48 responses were considered to be “blips”. The long-term consequences of this low-level transient viremia are uncertain, although cohort data suggest that this may be of minimal concern given its low magnitude.20 There was no correlation between patients experiencing a “blip” and elevated bilirubin levels.
A similar proportion of patients in each treatment group remained in the study at week 48. More patients receiving MVC permanently discontinued due to AEs, mainly hyperbilirubinemia. Rates of treatment-emergent AEs and SAEs were also very similar between the 2 groups; however, the incidence of grade 3 or 4 AEs was greater in the MVC group. In both treatment groups, the incidence of hyperbilirubinemia or potentially associated AEs was high, and rates were higher in the MVC group. This may be due to the drug–drug interaction between TDF and ATV that reduces exposure to ATV, with fewer patients needing to switch to an alternative boosted PI due to jaundice in this arm. The rate of jaundice (MVC, 16.7%) related to unconjugated hyperbilirubinemia was consistent with rates expected with the background regimen of ATV/r without TDF. As would be expected given the known profiles of the study drugs, the incidence of lipid abnormalities was very low.
It is reassuring that the numbers of protocol-defined treatment failures were similar between study arms and that no resistance or change in tropism was seen in those patients who were evaluated. Tropism was evaluated using the enhanced sensitivity Trofile assay, which can detect X4 variants in vitro in mixing experiments down to 0.3% of the total virus population,21 suggesting a lack of selective pressure from MVC, where one would expect early unmasking of minority X4-using variants. Of note, there were few patients with sufficient plasma HIV-1 RNA for resistance testing at the time of virological failure or discontinuation. In the patients with evaluable samples, resistance was not observed to any of the regimen components.
Several small studies that explored NRTI-sparing antiretroviral regimens using integrase inhibitors in treatment-naive patients have been reported. In the SPARTAN Study, 4/6 patients with virological failure while receiving unboosted ATV + raltegravir (RAL) demonstrated genotypic RAL resistance and 1 patient exhibited phenotypic resistance to RAL in the absence of genotypic evidence of resistance.25 Similarly, in the PROGRESS Study, which evaluated LPV/r + RAL twice a day vs LPV/r + TDF/FTC twice a day, 1/3 patients with virological failure in the RAL arm demonstrated genotypic resistance based on the N155H mutation in the integrase-encoding region, whereas 1/3 patients assessed for resistance in the NRTI arm had evidence of the reverse transcriptase M184V mutation.26 ACTG 5262 tested the dual-therapy regimen of RAL and DRV/r and showed that high plasma HIV-1 RNA at baseline was associated with increased rates of virological failure relative to a regimen of TDF/FTC and DRV/r.27 In this study, which included patients with renal dysfunction and NRTI and NNRTI resistance, integrase resistance was found in virus from 5/25 subjects treated with RAL in whom resistance testing was carried out.27 In contrast, the efficacy of the MVC arm compared with the TDF/FTC arm in the present study was relatively unaffected by resistance. Furthermore, the absence of development of on-treatment resistance observed in the current study, and other pilot studies exploring the use of MVC 150 mg once daily with a boosted PI,28 (S. Nozza, MD, personal communication, 2011) suggests that resistance with virological failure will prove to be less likely with MVC compared with other NRTI-sparing dual combinations. The potential for a MVC-containing regimen to lead to tropism change is worthy of discussion. In this study, no change was noted with the enhanced sensitivity Trofile assay. However, more recent phenotypic and genotypic assays have become available that assess tropism in peripheral blood mononuclear cells and so do not rely on viremia. Future studies should assess tropism evolution using these methods.
The current study was designed to be proof-of-concept/principle. Consequently, an appropriately powered confirmatory study will be required to test the applicability of a dual nucleoside/nucleotide-sparing regimen of MVC and boosted PI and to better define treatment differences between this regimen design and a standard 3-drug regimen.
In summary, these data show that a once-daily regimen of MVC + ATV/r results in viral suppression in the majority of treatment-naive patients with CCR5-tropic virus, with a low potential for resistance or loss of susceptibility to study drugs at treatment failure, and a safety profile that would be expected from the components of the regimen. The frequency of treatment-limiting hyperbilirubinemia was greater than expected, and hence future studies of MVC with boosted PIs will be using DRV.
This study was conducted by Pfizer Inc. Editorial support was provided by Clemence Hindley and Karen Irving at Complete Medical Communications.
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