The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml.
Arribas, Jose Ra; Horban, Andrzejb; Gerstoft, Janc; Fätkenheuer, Gerdtd; Nelson, Marke; Clumeck, Nathanf; Pulido, Federicog; Hill, Andrewh; van Delft, Yvoni; Stark, Thomasj; Moecklinghoff, Christianej
aHospital la Paz, Madrid, Spain
bWarsaw Hospital, Warsaw, Poland
cRigshospitalet, Copenhagen, Denmark
dUniversitat Köln, Germany
eChelsea and Westminster Hospital, London, UK
fCHU Saint-Pierre/Maladies Infectieuses, Brussels, Belgium
gHopital 12 de Octubre, Madrid, Spain
hPharmacology Research Laboratories, University of Liverpool, Liverpool, UK
iJanssen-Cilag EMEA, Tilburg, The Netherlands
jJanssen-Cilag EMEA, Neuss, Germany.
Received 13 August, 2009
Revised 13 October, 2009
Accepted 23 October, 2009
Correspondence to Jose R. Arribas, HIV Unit, Hospital la Paz, Castellana 261 28046, Madrid, Spain. Tel: +34 91 207 1676; fax: +34 91 729 0033; e-mail: firstname.lastname@example.org
Background: In virologically suppressed patients, darunavir-ritonavir (DRV/r) monotherapy could maintain virological suppression similarly to DRV/r and two nucleosides.
Methods: Two hundred and fifty-six patients with HIV RNA less than 50 copies/ml for over 24 weeks on current antiretrovirals [non-nucleoside reverse transcriptase inhibitor (NNRTI)-based (43%), or protease inhibitor-based (57%)], switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside reverse transcriptase inhibitors (NRTIs) (n = 129). Treatment failure was defined as two consecutive HIV RNA levels above 50 copies/ml (TLOVR) by week 48, or switches off study treatment. The trial had 80% power to show noninferiority for the monotherapy arm (delta = −12%).
Results: Patients were 81% male and 91% Caucasian, with mean age 44 years, and CD4 cell count of 574 cells/μl. In the primary efficacy analysis, HIV RNA less than 50 copies/ml by week 48 (per protocol) was 86.2 versus 87.8% in the monotherapy and triple therapy arms; by intent-to-treat switch equals failure, efficacy was 84.3 versus 85.3%; by a switch-included analysis, efficacy was 93.5 versus 95.1%: all three comparisons showed noninferior efficacy for DRV/r monotherapy. CD4 cell counts remained stable during the trial in both arms. One patient per arm showed at least one protease inhibitor mutation, and one patient in the triple therapy arm showed an NRTI mutation. Nine patients per arm discontinued randomized treatment for either adverse events or other reasons. No new or unexpected safety signals were detected.
Conclusions: In this study for patients with HIV RNA less than 50 copies/ml on other antiretrovirals at baseline, switching to DRV/r monotherapy showed noninferior efficacy versus triple antiretroviral therapy.
Combinations of two nucleoside analogues [nucleoside reverse transcriptase inhibitors (NRTIs)] with either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) are recommended as first-line treatment for HIV infection [1,2]. The primary aim of antiretroviral treatment is suppression of HIV RNA levels below 50 copies/ml, and current treatment guidelines recommend continuing combinations of at least three antiretrovirals for a patient's lifetime, even after full HIV RNA suppression below 50 copies/ml has been achieved [1,2].
Treatment with a single antiretroviral for patients with full HIV RNA suppression could improve tolerability, lower pill counts and costs, and could prevent resistance developing to other antiretroviral classes. However, a meta-analysis of previous clinical trials of protease inhibitor monotherapy, mainly with lopinavir/ritonavir, has shown significantly greater rates of treatment failure for lopinavir/ritonavir monotherapy versus three drug combinations . Despite this finding, the incidence of treatment emergent protease inhibitor drug resistance during protease inhibitor monotherapy has been very low, and most patients with low-level viraemia on protease inhibitor monotherapy can subsequently be re-suppressed by intensifying with nucleoside analogues [4,5].
The protease inhibitor darunavir has a high genetic barrier  and relatively long terminal elimination half-life with ritonavir (15 h) . In the ARTEMIS trial, darunavir/ritonavir (DRV/r) was evaluated in treatment-naïve patients at the dose of 800/100 mg once daily, combined with the nucleoside analogues tenofovir and emtricitabine: the DRV/r arm showed higher rates of HIV RNA suppression than the control protease inhibitor lopinavir/ritonavir at week 96 . DRV/r has also shown virological benefits over other protease inhibitors for treatment-experienced patients in the TITAN and POWER trials, used at the 600/100 mg twice daily dose [9,10].
The MONET trial was designed to evaluate whether the once-daily protease inhibitor darunavir/ritonavir could show noninferior efficacy to a triple therapy arm of two nucleoside analogues and darunavir/ritonavir, using a standardized efficacy endpoint of HIV RNA less than 50 copies/ml.
MONET is an ongoing, 144-week, randomized controlled, open-label phase 3b trial, with data obtained from 256 patients in 11 European countries, Russia and Israel. Patients were randomized between June 2007 and March 2008. The trial recruited patients who had HIV RNA levels below 50 copies/ml on a stable triple antiretroviral regimen, for at least 24 weeks, and no history of virological failure since first starting antiretrovirals.
Patients were randomized to receive DRV/r 800/100 mg once daily, either as monotherapy (monotherapy arm) or with two nucleoside analogues (triple therapy arm). The randomization was stratified for the use of non-nucleosides versus boosted protease inhibitors at screening. Darunavir was administered as 400 mg tablets, and ritonavir as 100 mg soft gelatin capsules. The nucleoside analogues used during the MONET trial were selected by the investigators and could be changed either at screening or during the trial.
Efficacy and safety assessments
Patients attended study visits at screening, baseline and then weeks 4, 12, 24, 36 and week 48. The frequency of visits (every 12 weeks) is similar to routine clinical practice. Plasma HIV RNA was measured using the Roche Amplicor HIV-1 Monitor assay (version 1.5, Roche Molecular Systems, Branchburg, USA). Viral genotypic tests were performed using Virco TYPE HIV-1 assays (Virco BVBA, Mechelen, Belgium). Genotypic drug resistance and PK drug levels were assessed for all patient samples with HIV RNA concentrations above 50 copies/ml. Virtual phenotyping was used to assess phenotypic sensitivity. Also, the number of patients with either IAS-USA major protease inhibitor mutations, or darunavir mutations , was analysed by treatment arm.
Any patient with an HIV RNA result above 50 copies/ml attended a confirmation visit within 2 weeks, for repeated testing of HIV RNA, drug resistance and plasma drug levels. If a patient had two consecutive HIV RNA levels above 50 copies/ml, investigators could intensify or change antiretrovirals. In addition, all patients were followed up to week 48.
Safety assessments included reported adverse events data, clinical laboratory tests (haematology, clinical chemistry, fasting lipids, and urinalysis), physical examination and anthropometric measurements. Clinical and laboratory abnormalities were classified using the Division of AIDS grading tables . An independent Data and Safety Monitoring Board (DSMB) reviewed interim efficacy and safety results.
Written informed consent was obtained from all participating patients before the study started. Study protocols were reviewed and approved by the appropriate institutional ethics committees and health authorities, and were undertaken in accordance with the Declaration of Helsinki.
The MONET trial was designed to show noninferior efficacy of the monotherapy arm versus the triple therapy arm at week 48, with a noninferiority margin of −12%. The sample size calculations assumed 80% power, a one-sided significance level of 0.025, a 90% overall response rate and 10% of patients excluded from the per protocol population. The primary efficacy parameter, treatment failure, was defined as two consecutive HIV RNA levels above 50 copies/ml at week 48, or discontinuation of randomized treatment [commonly known as time to loss of virological response (TLOVR)] .
In the primary analysis, switches of treatment classified as failure were either stopping darunavir/ritonavir, starting nucleoside analogues in the monotherapy arm, or stopping all nucleoside analogues in the triple therapy arm. Patients were allowed to switch nucleoside analogues for reasons of toxicity in the triple therapy arm.
The per protocol population was used for the primary efficacy analysis at week 48, consistent with CONSORT guidelines : this population excluded patients with major protocol violations such as a history of virological failure, or patients randomized incorrectly. The analyses were then repeated for the intent-to-treat (ITT) population, including all randomized patients. In the ITT – switch-included analysis – patients who had HIV RNA levels below 50 copies/ml at week 48 were counted as successes, even if they had confirmed HIV RNA elevations early in the trial or had discontinued from randomized treatment . In addition, the primary analysis was repeated, including only the observed virological endpoints (observed failure analysis).
Role of the funding source
The trial was designed and conducted by Janssen-Cilag EMEA Medical Affairs, a division of Janssen-Cilag International N.V., which is the study sponsor. The statistical analysis was conducted independently by an external statistician (Parexel International, France), and was reviewed and validated by a statistician at Janssen-Cilag (A.H.). The authors had full access to the data and the corresponding author had the final responsibility to submit the manuscript for publication.
Of 293 patients screened, 256 patients were randomized and treated (127 in the darunavir/ritonavir arm and 129 in the triple therapy arm) and were included in the ITT analysis (Fig. 1). One additional patient was randomized in error and never treated: this patient was excluded from all analyses. Ten patients were excluded from the per protocol population (four from the monotherapy arm, six from the triple therapy arm). Eight of these patients had a history of virological failure before the trial, one patient was imprisoned and one left the investigational site indefinitely. Data from 246 patients (123 per arm) were included in the per protocol population. All 256 patients in the ITT population were included in the safety analysis. Figure 1 shows the disposition of patients during the trial. Data were available for 255 of the 256 patients at week 48. Ten patients in the triple therapy arm switched their NRTIs during the trial, mainly for adverse events, but these patients are not considered as treatment failures in the analyses, because these switches were allowed in the protocol.
The patients were 81% male with a mean age of 44 years, mean weight of 73 kg and mean CD4 cell count of 574 cells/μl (Table 1). The patients had a median 8 years of known HIV infection, and had been treated with antiretrovirals for a median of 6.5 years.
At the screening visit, 57% of the patients were receiving protease inhibitors and 43% were receiving a non-nucleoside. Patients in the triple therapy arm were more likely to be on their first antiretroviral regimen (36%) than the patients in the monotherapy arm (23%). In addition, patients in the triple therapy arm were more likely to be protease inhibitor-naive (28%) than those in the monotherapy arm (23%). By hepatitis C serology, 22 (17%) patients had hepatitis C antibodies in the monotherapy arm and 12 (9%) in the triple therapy arm. At baseline, 13 patients had HIV RNA levels above 50 copies/ml (nine in the monotherapy arm and four in the triple therapy arm), despite having results below 50 copies/ml at screening; two of these elevations were above 400 copies/ml. These patients were still included in both the per protocol and ITT analyses.
Nucleoside analogues used at baseline in the triple therapy arm were either tenofovir and emtricitabine (46%), tenofovir and lamivudine (7%), abacavir and lamivudine (31%), or zidovudine and lamivudine (10%), with 6% taking other combinations.
In the primary per protocol, switch equals failure analysis, 86.2% had HIV RNA less than 50 copies/ml at week 48 in the monotherapy arm, versus 87.8% in the triple therapy arm (Table 2 and Fig. 2). In the ITT, switch equals failure analysis, 84.3% of patients in the monotherapy arm and 85.3% in the triple therapy arm had HIV RNA less than 50 copies/ml at week 48. Both treatment comparisons met the predefined criteria to show noninferiority for monotherapy versus the triple therapy arm. In the ITT, switch-included analysis, 93.5% of patients in the monotherapy arm, and 95.1% in the triple therapy arm, had HIV RNA levels below 50 copies/ml at the week 48 visit. The two observed failure analyses, including only the virological endpoints (Table 2), showed suppression rates above 90% in both treatment arms. Median CD4 cell counts remained stable over time in both treatment arms.
Outcomes of treatment failures
Tables 3–6 show the outcomes for each individual patient with protocol-defined treatment failure. Of the 20 patients with treatment failure in the monotherapy arm, 18 (90%) had HIV RNA levels below 50 copies/ml at week 48 (Tables 3 and 4). Of the 19 patients with treatment failure in the triple therapy arm, 17 (89%) had HIV RNA levels below 50 copies/ml either at week 48 or at their most recent visit (Tables 5 and 6). Most of the repeated HIV RNA elevations were transient, in the range of 50–200 copies/ml, and happened at times of poor adherence or intercurrent infections. In the monotherapy arm, seven of the 11 patients with confirmed HIV RNA elevations changed their antiretrovirals as recommended in the trial protocol, either by adding NRTIs, or switching back to their pretrial antiretrovirals. None of the seven patients in the triple therapy arm with confirmed HIV RNA elevations changed their antiretroviral treatment.
In multivariate analysis, hepatitis C co-infection was a significant predictor of confirmed HIV RNA elevations (P < 0.01). At baseline, more patients were hepatitis C virus (HCV) antibody positive in the DRV/r arm (17%) than in the control arm (9%). For patients infected only with HIV, the percentage with HIV RNA less than 50 copies/ml at week 48 (primary efficacy analysis) was 89.2% in the monotherapy arm versus 88.2% in the triple therapy arm. For patients who were antibody-positive for both HIV and HCV, the percentage with HIV RNA below 50 copies/ml at week 48 was 71% in the monotherapy arm versus 83.3% in the triple therapy arm. Two additional patients had acute HCV infection during the trial (in the monotherapy arm): both had HIV RNA elevations at the time of acute HCV infection.
Genotypic data were available for 35 of 61 (57%) patients with at least one HIV RNA result above 50 copies/ml (22 and 13 patients in the monotherapy and triple therapy arms, respectively). Thirty-three of these patients showed genotypic and phenotypic sensitivity to all boosted protease inhibitors and NRTIs. One protease inhibitor-pretreated patient in the triple therapy arm had a single genotype, showing resistance to lamivudine (M184V) and to protease inhibitors (V82IT, L90M), when the HIV RNA level was 78 copies/ml. However, the virus was phenotypically sensitive to DRV/r (fold change = 1.2). All subsequent visits showed HIV RNA levels below 50 copies/ml. Also, one protease inhibitor-pretreated patient in the monotherapy arm had a single DRV mutation (L33F), when the HIV RNA level was 63 copies/ml at one visit (week 12). However, the virus was phenotypically sensitive to DRV (fold change = 0.8) and HIV RNA was suppressed below 50 copies/ml for this patient for all subsequent visits to week 48.
No new or unexpected safety events occurred, and adverse events were not treatment-limiting in most cases. Serious adverse events were seen in 18 patients (nine in each treatment arm). The most common grade 2–4 drug-related clinical adverse events were gastrointestinal. By week 48, eight patients in the monotherapy arm and three patients in the triple therapy arm had discontinued study medication for adverse events – these were mainly gastrointestinal adverse events. No patients died during the trial.
Neurological or psychiatric adverse events were analysed in detail, given concerns over the CNS penetration of protease inhibitors. Grade 1–4 adverse events of the nervous system were seen in 16% of patients in each treatment arm, whereas grade 1–4 psychiatric adverse events were seen in 9% of patients in each treatment arm. One patient in the monotherapy arm discontinued darunavir for grade 3 headache, considered to be drug-related. One patient in each arm developed grade 2 rash, considered drug-related, but no patients discontinued the trial for rash.
The most common laboratory abnormalities were elevations in lipids and liver enzymes. Six patients in the monotherapy arm and two in the triple therapy arm had grade 3 elevations in alanine aminotransferase and/or aspartate aminotransferase: these patients all had either acute infection with HCV (two cases), presence of HCV antibodies (five cases) or acute hepatitis A infection (one case). Six of these eight patients showed transient elevations in liver enzymes, with values at grade 1 or below at week 48. There were five patients in the monotherapy arm and two in the triple therapy arm who had treatment emergent grade 3 elevations in total cholesterol, sustained for at least two consecutive visits. Patients who started tenofovir at baseline in the triple therapy arm showed mean falls in total cholesterol of 0.5 mmol/l (25 mg/dl), whereas patients who stopped taking tenofovir at baseline in the monotherapy arm showed similar rises in total cholesterol by week 4.
There were more haematological abnormalities in the triple therapy arm. For example, 42.6% of patients in the triple therapy arm had at least one red blood cell result below the lower limit of normal (<4.12 × 1012/l), versus 22.8% in the monotherapy arm. Haematological abnormalities were mainly associated with zidovudine treatment. Patients in the triple therapy arm who continued to take zidovudine showed persistently low red blood cell counts, whereas those who stopped zidovudine at baseline showed rapid rises in red blood cell count, to levels similar to patients taking other nucleosides.
MONET is the first randomized trial of ritonavir-boosted protease inhibitor monotherapy to show noninferior efficacy versus triple antiretroviral drug treatment. The MONET trial used a standard efficacy endpoint of HIV RNA suppression below 50 copies/ml, with switches off randomized treatment classified as failure . In the monotherapy arm, 18 of the 20 patients who either showed elevations in HIV RNA or discontinued darunavir treatment subsequently had HIV RNA levels less than 50 copies/ml at week 48. The risk of drug resistance was minimal. Noninferior efficacy was shown for the monotherapy despite the less favourable baseline characteristics in this treatment arm, in particular, more patients were co-infected with hepatitis C, which was an independent predictor of confirmed HIV RNA elevations during the trial. Results from the primary efficacy analysis were supported by several sensitivity analyses, which also showed noninferior efficacy for DRV/r monotherapy. The HIV RNA elevations seen were mainly transient, in the range of 50–200 copies/ml, and generally did not lead to treatment-emergent drug resistance. These minor elevations in HIV RNA may be associated with temporary poor adherence, intercurrent infections or the variability of the HIV RNA PCR assays [16,17]. Clinical trials conducted by the AIDS Clinical Trials Group (ACTG) in USA are starting to use an HIV RNA endpoint of 200 copies/ml .
In both arms, the main reason for discontinuing DRV/r was for gastrointestinal side-effects. The MONET trial was not designed to show a safety benefit to stopping nucleoside analogues – these could be changed either at baseline or during the trial in the triple therapy arm. In the MONET trial, the use of zidovudine was associated with more haematological abnormalities, consistent with previous experience . There is also the potential to prevent other adverse events with protease inhibitor monotherapy. A recently reported comparison of tenofovir-emtricitabine with abacavir-lamivudine in 360 suppressed patients has shown improved lipids for patients in the tenofovir arm, but also showed some evidence for excess osteopenia for use of tenofovir . Use of abacavir may be associated with an increased cardiovascular risk in cohort studies . Stavudine is still widely used in developing countries, but is associated with lipoatrophy and lipid elevations . Virological failure of first-line NNRTI-based treatment can lead to the emergence of NRTI and NNRTI resistance , which could be prevented by use of DRV/r monotherapy.
There is a concern that the penetration of protease inhibitors into the CNS may not be sufficient to prevent replication of HIV in this compartment. However, clinical data to support this concern are lacking, and darunavir does show levels in the CNS above the EC50 . In the MONET trial, the incidence of neurologic or psychiatric adverse events was the same in the monotherapy and triple therapy arms, but longer-term follow-up is needed to confirm these results. Other clinical trials of DRV/r monotherapy are ongoing.
The MONET trial recruited patients with HIV RNA levels below 50 copies/ml for over 24 weeks at baseline, and who then switched from other antiretroviral treatments. These results cannot predict the efficacy of DRV/r monotherapy as a first-line treatment. Lopinavir/ritonavir monotherapy showed unfavourable results for first-line treatment in the MONARK trial ; a switch to lopinavir/ritonavir monotherapy after short-term undetectability showed lower efficacy than efavirenz-based HAART in the Abbott 613 trial . Clinical trials of other boosted protease inhibitors are limited: two pilot studies of atazanavir/ritonavir have shown mixed results [27,28]. In contrast with the results of the OK04 trial , a recent study of lopinavir/ritonavir monotherapy of patients with suppressed HIV RNA at baseline was stopped after excess rates of virological failure were seen, correlated with low pretreatment nadir CD4 cell counts . The success of darunavir/ritonavir in the MONET trial may be related to the potency, half-life and safety profile of darunavir [6–8], but the results needs to be confirmed in longer-term follow-up and in other clinical trials.
In summary, once-daily DRV/r monotherapy has shown noninferior HIV RNA suppression at week 48 (85.4%) compared with a standard control arm of two nucleosides and DRV/r (86.4%). Almost all patients on DRV/r monotherapy had full HIV RNA suppression, at week 48 in the MONET trial: although this strategy warrants further evaluation, these data suggest that a switch to DRV/r monotherapy can be considered in treatment-experienced patients who have a history of HIV RNA levels below 50 copies/ml on other treatments, but who are wishing to avoid toxicities related to nucleoside analogues, non-nucleosides or other antiretrovirals.
We thank the investigators, study coordinators, site and data managers and the patients for their contributions.
J.R.A. is an investigator from the Programa de Intensificación de la Actividad Investigadora en el SNS (I3SNS) 2008, INT07/147.
Funding: Janssen-Cilag EMEA. Clinicaltrials.gov identifier: NCT00458302. Conflict of interest: J.R.A. has received consultancy payments, grant support and speaking fees from Janssen Cilag which is responsible for darunavir (the study drug) in Europe.
Contributors: J.A., T.S., C.M. Y.D. and A.H. provided scientific input into the study design and study protocol. J.A., A.H. and C.M. assisted in writing the first draft of the manuscript. All authors assessed clinical data from the study and reviewed and edited the manuscript. All investigators were involved in enrolment of patients. A.H. conducted the statistical analyses.
MONET Study Team: Austria: A. Rieger, B. Gmeinhart (Vienna); N. Vetter, M. Gartner (Vienna). Belgium: N. Clumeck, K. Kabeya (Brussels); E. Florence, J. Hoste (Antwerp). Denmark: J. Gerstoft (Copenhagen), C. Pedersen (Odense), L. Mathiesen (Hvidovre). Germany: G. Fätkenheuer, T. Kümmerle (Cologne); A. Stoehr, M. Sabranski (Hamburg), H. Schmidt, C. Mayr (Berlin); M. Stoll, Y. The (Hannover); C. Stephan, P. Khaykin (Frankfurt). Hungary: D. Banhegyi, J. Szlavik (Budapest). Israel: S. Maayan, D. Shasha (Jerusalem). Italy: A. Lazzarin, N. Gianotti (Milan); A. Antinori, S. Mosti (Rome); F. Suter, D. Ripamonti (Bergamo); G. Carosi, P. Nasta (Brescia); A. D'Arminio Monforte, T. Bini (Milan). Poland: A. Horban, P. Pulik (Warsaw). Portugal: F. Antunes, M. Doroana (Lisbon); R. Marques, M. del Carmen Pinero (Porto). Russia: V. Pokrovsky, O. Yurin (Moscow); N. Zakharova, Z. Guba (St Petersburg). Spain: B. Clotet, J.R. Santos (Barcelona); F. Pulido, S. Fiorante (Madrid); J. Arribas, M. Montes (Madrid); J. Gatell, A. Milinkovic (Barcelona); J. Iribarren, M. Aramburu (Donostia); R. Rubio, J. Llenas (Madrid); J. Pasquau, C. Garcia (Granada). Switzerland: P. Vernazza, P. Schmid (St Gallen). UK: M. Johnson, Z. Cuthbertson (London); B. Peters, M. Perry (London); M. Nelson, C. Higgs (London); A. Winston, L. Garvey (London).
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Inhibitors of HIV-1 Entry
Current Pharmaceutical Design, 19():
Enfermedades Infecciosas Y Microbiologia ClinicaNew strategies in the optimisation of lopinavir/ritonavir doses in human immunodeficiency virus-infected patientsEnfermedades Infecciosas Y Microbiologia Clinica
From TMC114 to Darunavir: Five Years of Data on Efficacy
AIDS Reviews, 15(2):
Journal of the International AIDS SocietySwitching to darunavir/ritonavir monotherapy (DRV/r mx): effect on kidney function and lipid profileJournal of the International AIDS Society
Journal of Antimicrobial ChemotherapySafety and feasibility of treatment simplification to atazanavir/ritonavirlamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitorsatazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study)Journal of Antimicrobial Chemotherapy
Journal of Antimicrobial ChemotherapyProtease inhibitor-based antiretroviral therapy in treatment-naive HIV-1-infected patients: the evidence behind the optionsJournal of Antimicrobial Chemotherapy
darunavir-ritonavir; maintenance; monotherapy
© 2010 Lippincott Williams & Wilkins, Inc.
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