Highly active antiretroviral therapy (HAART) has increased the life expectancy of persons with HIV, and thus, chronic conditions, such as chronic hepatitis B (CHB), are becoming more important [1–3]. CHB affects an estimated 10% of the HIV-positive population worldwide and is a major contributor to morbidity and mortality in this population .
Treating hepatitis B virus (HBV)/HIV coinfected patients is complicated. HIV infection may alter intrinsic immune responses to HBV, leading to higher rates of chronicity, decreased rates of HBeAg seroconversion, and increased HBV replication [5,6]. If HBV and HIV therapy are initiated together, tolerability and treatment convenience become considerations because HIV-infected patients often take complex treatment regimens for extended periods and adherence to prescribed therapy is critical for long-term success. The potential for drug–drug interactions is increased if both viruses are treated simultaneously in part, due to the associated liver toxicity of some anti-HIV medications [7–9]. Several agents approved for HIV treatment are active against HBV but pose a risk for development of resistance in both viruses. Data from controlled clinical trials in HIV/HBV coinfected patients are scarce and preliminary treatment guidelines exist for HBV infection in these patients, but are based largely on data from mono-infected patients [7,10].
When this study was initiated, only three agents were licensed for CHB treatment: interferon alpha, lamivudine, and adefovir. Data on interferon alpha in treating CHB in HIV coinfected patients suggest a lower rate of response than in mono-infected individuals . Lamivudine, a common component of HAART, was the first nucleoside analog approved for the treatment of HBV, but has inadequate potency against HIV as a single agent and carries the risk of resistance selection in both HIV and HBV . Lamivudine resistance in HBV occurs more rapidly in HIV/HBV coinfected patients versus HBV mono-infected patients, with incidences of 50% after 2 years and 90% after 4 years . Lamivudine-resistant HBV is associated with disease progression , and continuation of lamivudine in patients with lamivudine-resistant HBV has been shown to offer no clinical benefit . Adefovir dipivoxil (a prodrug of adefovir) is also active against both HIV and HBV but is not licensed for use against HIV, because its effective dose is limited by nephrotoxicity. In a 48-week pilot study of adefovir in 31 HBV/HIV coinfected patients with prior lamivudine resistance, adefovir resulted in a mean decrease in serum HBV DNA of log 4.01 copies/ml at week 48, persisting through 144 weeks [16,17]. Although adefovir was generally well tolerated, 15 patients experienced a transient increase in serum alanine aminotransferase (ALT) during the first 48 weeks.
Entecavir is a potent inhibitor of HBV replication, active against both wild-type and lamivudine-resistant HBV. In a phase III study in lamivudine-refractory CHB patients, switching to entecavir provided superior histologic improvement, viral load reduction, and ALT normalization compared with continued lamivudine, with a comparable adverse event profile . Entecavir is a weak inhibitor of mitochondrial DNA polymerases, and does not interact with antiretroviral agents . This report is of a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of entecavir in HIV/HBV coinfected adults with HBV viremia while on lamivudine-containing HAART with effective HIV RNA suppression.
This study enrolled HIV/HBV coinfected men and women (≥16 years of age), with no evidence of hepatitis C virus or hepatitis D virus infection, who had been on lamivudine-containing HAART for at least 24 weeks before enrollment, or who were infected with HBV carrying a lamivudine-resistance-associated mutation (rtM204V/I and/or rtL180M). The HBV reverse transcriptase gene was amplified by polymerase chain reaction (PCR) from serum DNA and sequenced at study entry and week 48. Patients were hepatitis B surface antigen (HBsAg)-positive for at least 24 weeks before screening; were hepatitis B e antigen (HBeAg)-positive or (HBeAg)-negative; and had serum HBV DNA at least 105 copies/ml at least 4 weeks prior to screening and at screening). Screening ALT was no more than 10 times the upper limit of normal (ULN), and patients needed to have compensated liver disease. Serum HIV RNA was <400 copies/ml at least 12 weeks before screening and again at screening, but baseline levels may have differed. Concomitant medications with activity against HBV (other than lamivudine) were not permitted. Twenty-eight sites in Europe, South America, and the United States participated.
This was a prospective, randomized, double-blind, placebo-controlled phase 2 study. Eligible patients were randomized to either entecavir 1 mg once daily or placebo (Fig. 1) in a 2: 1 ratio using a permuted block design. Randomization was stratified by site, but most sites randomized fewer than six patients (i.e., the block size for the planned 2: 1 randomization scheme), leading to a higher than planned entecavir: placebo ratio (i.e., a 3: 1 ratio). Patients received the first dose of study medication within 72 hours of randomization.
All patients continued their lamivudine (300 mg q.i.d.)-containing HAART regimens, which could be adjusted as needed (except for tenofovir disoproxil fumarate and emtricitabine, which were prohibited). Patients received blinded treatment for 24 weeks, after which time they were offered open-label entecavir 1 mg once daily for another 24 weeks. Written informed consent was obtained from all patients, and each study site obtained independent ethics committee/institutional review board approval. The study was conducted in accordance with the principles of the Declaration of Helsinki and was consistent with good clinical practice and applicable local regulatory requirements.
Efficacy end points
HBV DNA was measured in serum by Roche Amplicor PCR assay (limit of quantitation =300 copies/ml) at a central laboratory (Quintiles Laboratories Ltd, Smyrna, Georgia) at weeks 2, 12, 24, and 48. The primary end point of the study was the mean change from baseline in HBV DNA level by PCR assay (log10 copies/ml) at week 24. Secondary end points included mean change in serum HBV DNA adjusted from baseline at week 48; and the proportion of patients with HBV DNA less than 300 copies/ml at weeks 24 and 48, the proportion of patients with ALT normalization (≤1.0 × ULN) at weeks 24 and 48, and the proportion of patients with seroconversion (loss of HBeAg and gain of antibody to HBeAg [HBeAb]) among HBeAg(+) patients at weeks 24 and 48.
Safety end points
The primary safety end point was the proportion of patients who discontinued study drug due to adverse events or laboratory abnormalities. Other safety evaluations included the proportion of patients experiencing an HIV RNA rebound (from <400 copies/ml to confirmed >1000 copies/ml) at weeks 24 and 48; the mean change in CD4 cell count from baseline at weeks 24 and 48; the proportion of patients with increases (greater than two-fold and greater than three-fold) in serum ALT, aspartate aminotransferase (AST); and total bilirubin, as well as analyses of adverse events, serious adverse events (SAEs), and deaths.
HBV drug resistance analysis
HBV DNA samples from all treated patients were analyzed at baseline for substitutions associated with lamivudine resistance (M204V/I and L180M) by direct sequencing. Week 48 samples from all entecavir-treated patients were subsequently monitored for evidence of emerging resistance substitutions. HBV DNA was extracted by PCR, amplified, and amino acids 1–344 of the reverse transcriptase were sequenced as described elsewhere . Susceptibility assays on all emerging substitutions were conducted in HepG2 cells transfected with recombinant viruses.
Data analysis and statistics
A total sample size of 60 patients, 40 of whom were randomized to the entecavir arm and 20 to the placebo arm, would provide 85% power to demonstrate superiority in mean change in serum HBV DNA at week 24 compared with baseline, assuming a treatment difference of 1.4 log10 copies/ml, a standard deviation of 1.6 and a two-sided significance level of 0.05. A sample size ratio of 2: 1 for entecavir versus placebo was chosen to collect additional safety and efficacy data in the entecavir arm, and to limit the number of patients potentially exposed to a virologically failing anti-HBV treatment (placebo).
Treatment group comparisons for the primary end point and other continuous variables used t-tests from linear regression models with covariates for treatment group and baseline measurement. The principal method for missing data was to include only patients with baseline and week-24 measurements (i.e., evaluable patients). Serum HBV DNA was evaluated as a continuous variable on the log10 scale through week 24. Binary variables (proportions of patients with HBV DNA <300 copies/ml, loss of HBeAg, seroconversion and ALT normalization) were summarized by counts and percentages. Confidence intervals (CI) for differences in proportions were based on the normal approximation to the binomial distribution, with unpooled proportions used in the computation of the standard error of the difference. Tests were based on the corresponding one degree-of-freedom χ 2 test. The principal method for handling missing data for the proportion analyses was as follows: noncompleter = failure (i.e., NC = F).
The study enrolled 109 patients, of whom 68 were randomized to blinded treatment and received at least one dose of study drug (see Fig. 1). The first patient was enrolled in September 2002, and the last one completed the blinded treatment in May 2004. Three patients in the entecavir group did not complete 24 weeks of blinded treatment: one patient had ongoing serum HBV DNA reduction and ALT normalization, but the investigator labeled the reason for discontinuation as ‘lack of efficacy’. Two patients discontinued due to adverse events that began at baseline: one due to elevated hepatic enzyme and serum bilirubin and one due to elevated ALT/AST. All patients who completed 24 weeks of blinded treatment continued into the open-label entecavir phase, and all but one (who was lost to follow-up) completed treatment to week 48. The two treatment groups were well balanced with respect to demographics and HBV and HIV disease characteristics (Table 1). The majority of patients were HBeAg-positive (99%) and were infected with HBV carrying lamivudine resistance-associated mutations (95%) at baseline. The mean time on lamivudine therapy before study entry was 4.5 years.
HBV DNA response
The mean HBV DNA in entecavir-treated patients was 5.52 log10 copies/ml versus 9.27 log10 copies/ml for placebo at week 24, and 4.79 log10 copies/ml versus 5.63 log10 copies/ml, respectively, at week 48. As Fig. 2 shows, entecavir treatment resulted in a rapid reduction in serum HBV DNA, with superiority versus placebo observed as early as 2 weeks (mean change from baseline for entecavir [–1.55 ± 0.14 log10 copies/ml] versus placebo [+0.05 ± 0.13 log10 copies/ml]; estimated difference −1.60 log10 copies/ml [95% CI −2.10, −1.09; P < 0.0001]). At week 24, mean changes from baseline for the entecavir (48 evaluable patients) and placebo (16 evaluable patients) groups were −3.65 and +0.11 log10 copies/ml, respectively, an estimated difference of −3.76 log10 copies/ml (95% CI −4.49, −3.04; P < 0.0001). For patients initially randomized to entecavir, the mean change from baseline in HBV DNA continued to increase during the open-label entecavir phase, reaching −4.20 log10 copies/ml at study week 48. Patients initially randomized to placebo in the double-blind phase experienced a mean change of −3.56 log10 copies/ml in HBV DNA at week 48 (i.e., after 24 weeks of entecavir treatment).
Six percent (3/51) of entecavir-treated patients, and no placebo recipients, achieved HBV DNA levels less than 300 copies/ml at week 24. At week 48, 8% (4/51) of patients initially randomized to entecavir and none of those who originally received placebo, achieved HBV DNA levels less than 300 copies/ml.
Serologic and biochemical responses
Among patients with an abnormal ALT at baseline, ALT normalization to 1.0 × ULN or less was observed in 34% of patients in the entecavir group and 8% of the placebo group at week 24 (P = 0.08) and in 37% of patients in the entecavir group and 46% of patients originally randomized to placebo at week 48. Loss of HBeAg occurred in one (2%) entecavir patient by week 48 and in no placebo patients (P = 0.56). HBeAg seroconversion occurred in one patient (2%) in the entecavir group at week 24, and no further seroconversions occurred by week 48.
Among the 68 patients randomized to treatment (entecavir = 51; placebo = 17), more than 95% had lamivudine-resistance substitutions M204I/V ± L180M at baseline as determined by sequencing. Genotypic analysis of paired baseline and 48-week samples was performed in 43 of the 47 entecavir-treated patients who completed 48 weeks of entecavir. Emerging substitutions associated with entecavir resistance were detected in two patients (5%). Both had M204I/V + L180M at study entry, with emergence of entecavir resistance substitutions S202C or T184S detected by week 48. No patient treated with entecavir experienced a virologic breakthrough during the first 48 weeks of treatment.
The overall frequency of adverse events was comparable between the entecavir (86%) and placebo (82%) groups during blinded treatment. The most frequently reported adverse events are shown in Table 2.
As expected in patients with CHB and concomitant treatment with anti-HIV agents, elevations of ALT and AST greater than two times the baseline values were frequently reported in both groups. ALT elevations greater than two times the baseline values and greater than 10 × ULN (ALT flares) were observed in two patients on entecavir. Both cases occurred during the double-blind phase and did not lead to treatment discontinuation. Although additional increases in ALT occurred, no additional ALT flares were observed during open-label entecavir treatment.
Serious adverse events were reported for one patient (in the entecavir group) during blinded treatment (hepatic encephalopathy reported on day 5 of therapy and bleeding by esophageal varices reported on day 44 of therapy) and for four patients (6%) during the open-label treatment phase that continued from the double-blind treatment phase (one patient each had acute myocardial infarction, pneumonia, testicular neoplasm, and esophageal varices/hemorrhage). All of these SAEs were considered by the investigators to be either not related or not likely related to study drug. No deaths were reported.
Two patients (4%) in the entecavir group discontinued treatment because of adverse events (elevated hepatic enzyme and blood bilirubin, and elevated ALT/AST [previously described for one of these patients]). For both patients, the liver function test abnormalities began at baseline and led to study discontinuation. These adverse events were considered unrelated to study medication.
No clinically relevant changes in mean CD4 cell counts were observed on treatment through week 48 (Table 3). In the entecavir group, the mean CD4 cell counts increased from 508 cells/μl at baseline to 567 cells/μl at week 48, and in the placebo group counts decreased from 520 to 485 cells/μl. No patient experienced a rebound in HIV RNA during the study. As shown in Table 3, no meaningful changes in mean HIV RNA levels or changes from baseline were observed through week 48. A total of seven patients (four in the entecavir group, two in the placebo group, and one during the open-label phase) received both entecavir and abacavir; no significant changes in HIV RNA were observed in these patients compared with the overall populations.
The increasing prevalence of HIV/HBV coinfection and the complications associated with treating HBV in this population highlights the importance of data from controlled clinical trials in coinfected patients [1–4]. Treating HBV in HIV-infected patients is challenging, because these patients are immunocompromised and, therefore, less able to mount an immune response and control viral replication. They may also exhibit lamivudine-refractory HBV disease, because they often have been treated with lamivudine for an extended period for their HIV infection. The emergence of lamivudine-resistant HBV mutations increases with treatment duration. After 1 year of lamivudine therapy for HBV in non-HIV infected patients, 16–32% develop HBV lamivudine resistance, and after 4 years the number increases approximately to 70% [21,22]. Resistance develops even more rapidly in HIV/HBV coinfected patients, with 50% of patients developing resistance after 2 years and 90% after 4 years . The emergence of resistance mutations complicates treatment decisions and compromises outcomes [13,21,22].
The patients in this study were coinfected with HIV (mean CD4 cell count: 514 cells/μl at baseline), had a high HBV DNA level at baseline (mean 9.13 log10 copies/ml), and had failed high-dose lamivudine (300 mg/day; 4.5 years mean treatment duration). Approximately 95% of patients with an available baseline sample showed at least one mutation in the HBV polymerase associated with lamivudine resistance. Despite this complex clinical setting, entecavir demonstrated substantial efficacy against HBV, low genotypic resistance, and no confirmed virologic breakthrough through 48 weeks of entecavir treatment. The mean change in serum HBV DNA from baseline was −3.65 log10 copies/ml after 24 weeks of blinded treatment with 1 mg of entecavir added to lamivudine. Antiviral HBV efficacy was observed as early as week 2 (mean change from baseline HBV DNA was −1.55 log10 copies/ml) and HBV DNA continued to decrease, achieving a mean change of −4.20 log10 copies/ml at week 48. Although genotypic resistance was seen only in two patients with prior lamivudine resistance in this study, in patients with lamivudine-resistant virus, the risk of entecavir-resistance may increase with longer follow-up. In a 4-year analysis of HBV mono-infected lamivudine-refractory patients treated with entecavir, the cumulative virologic breakthrough due to entecavir was 1, 11, 27 and 39% in years 1, 2, 3 and 4, respectively . These results also suggest that in lamivudine-resistant patients, particular those who are HBV/HIV coinfected, the use of combination therapy for both HIV and HBV may demonstrate less resistance.
Although a low percentage of patients achieved HBV DNA less than 300 copies/ml and HBe seroconversion, this study is consistent with other studies in similar patients. In a study in 35 HIV/HBV coinfected patients receiving HAART, adefovir resulted in HBV DNA less than 300 copies/ml in 25% of patients after 144 weeks of treatment; similar to the present study, the median serum HBV DNA at baseline was high (9.76 log10 copies/ml) . A study of tenofovir treatment in 20 HIV/HBV coinfected patients [median baseline HBV DNA viral load: 181 500 000 GEq/ml (interquartile range: 47 375 000–755 000 000 GEq/ml]) and a median of 108 weeks lamivudine experience resulted in a 4-log10 reduction in HBV DNA levels after 52 weeks . Furthermore, studies have shown that only 9% of patients treated with adefovir and 11% treated with tenofovir achieve HBeAg loss [17,25]. In the tenofovir study of 20 HIV/HBV coinfected patients, only five patients (25%) underwent HBe seroconversion during the study period . Although none of the aforementioned studies examined liver histology, the changes in HBV DNA levels observed with these agents are expected to result in improvements based on numerous studies that have shown delayed progression of disease as a result of treatment [26–28].
Elevation of serum ALT is associated with lamivudine-resistant HBV in HIV coinfected persons . The addition of adefovir to lamivudine in a population similar to this study resulted in normalization of ALT in 14% of patients at week 48, and 70% of patients by week 144 . Entecavir also normalized ALT in 37% of entecavir-treated patients at week 48 (for patients with baseline ALT greater than 1.0 × ULN). It is important to note that 80% of patients in this trial received at least one antiretroviral agent associated with liver toxicity and hypertransaminasemia (nevirapine, ritonavir, lopinavir, stavudine, and didanosine). Signs of serious liver toxicity were uncommon in this study, suggesting that adding entecavir to antiretroviral therapy was generally well tolerated. Also, there were neither signs of interaction nor interference between entecavir and abacavir (both guanosine analogs) with respect to liver toxicity in the few patients who received both drugs (n = 7).
The overall safety profiles of entecavir and placebo were comparable during blinded treatment, with a similar frequency of adverse events. Entecavir remained generally safe and well tolerated over the open-label dosing phase. Self-limited ALT flares and hepatic SAEs were infrequent, and no new ALT flares occurred during the open-label period. Nucleoside/nucleotide analogs may interfere with mitochondrial DNA, leading to adverse events such as lactic acidosis. This is of concern, because HIV/HBV coinfection may require use of more than one nucleoside/nucleotide analog. Previous in-vitro data demonstrated no activity on human mitochondrial (gamma) polymerase with entecavir . In this small study, no cases of lactic acidosis or symptomatic hyperlactatemia were observed.
Previous in-vitro cell culture assays evaluated entecavir and either abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine and showed that these nucleoside analogs were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In comparable HIV antiviral assays, entecavir at micromolar concentrations was not antagonistic to the anti-HIV activity in cell culture of these nucleoside analog reverse transcriptase inhibitors or emtricitabine. Also, in drug–drug interaction studies in healthy volunteers of entecavir coadministered with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate, the steady-state pharmacokinetics of each drug were not altered with coadministration. The present trial confirmed no evidence that entecavir interferes with the safety or efficacy of several HAART regimens.
Entecavir has not been evaluated in HIV/HBV coinfected patients who are not concurrently receiving effective HIV treatment. Limited clinical experience suggests a potential for the development of resistance in HIV reverse transcriptase if entecavir is used to treat chronic hepatitis B infection in patients with HIV infection not being treated. Therefore, entecavir is not recommended for HIV/HBV coinfected patients who are not receiving HAART [19,30].
In summary, these results demonstrate entecavir's tolerance and efficacy in the treatment of CHB in patients coinfected with HIV and HBV who experienced HBV viremia while on lamivudine therapy. Therefore, entecavir may provide clinical value when HBV DNA levels remain elevated despite HAART therapy.
Data presented in part at the 45th Interscience Conference of Antimicrobial Agents and Chemotherapy, December 16–19, 2005, Washington, District of Columbia (abstract H-415), and at the 12th Conference on Retroviruses and Opportunistic Infections, February 22–25, 2005, Boston, Massachussets (abstract 123), 13th Conference on Retroviruses and Opportunistic Infections, February 5–9, 2006, Denver, Colorado (poster 832).
Financial support: This study was supported by a research grant from Bristol-Myers Squibb.
M.G.P. had full access to all data in the study and had final responsibility for the decision to submit for publication, participated in data collection, data analysis and interpretation, and drafting of the manuscript. B.G. participated in data collection, data analysis and interpretation, and drafting of the manuscript. A.H. participated in the data collection, data analysis and interpretation, and drafting of the manuscript. C.E.B.-M. participated in data collection, data analysis and interpretation, and drafting of the anuscript. I.C. participated in data collection, data analysis and interpretation, and drafting of the manuscript. M.C.M.-C. participated in data collection, data analysis and interpretation, and drafting of the manuscript. V.S. participated in data analysis and interpretation, and drafting of the manuscript. P.P. participated in data analysis and interpretation, and drafting of the manuscript. A.H. participated in the data analysis and interpretation, and drafting of the manuscript. H.B.-S. participated in data analysis and interpretation, and drafting of the manuscript.
In addition to the authors, the following investigators participated in the study.
South American Investigators: O. Abaurre, M. Agostini, D. Baraldo, J. Benetucci, F. Bessone, E. Boccardo, M. Castro Boulos, I. Cassetti, O. Conceicao, M. Mendes-Corrêa, M. Stockler de Almeida, F.K. Dias do Prado, L. Duarte, H. Fainboim, L. Martins Filho, R. Focaccia, A. Gadano, V. Galante, J. Galindez, M. Galvan, M. Gonzalez, C. Guatini, L. Gutierrez, H. Hoet, M. Ishida, E. Jukemura, J. Lazovski, H. Li, R. Lorenco, S. Lupo, R. Marino, C. Brandã-Mello, C. Ochoa, U. Oliveira, G. Ortega, M. Pessôa, M. Amendola Pires, R. Quercia, P. Ramos, T. Reuter, L. Rodriguez, R. Salazar, E. Bortholi Santos, C. Zala.
North American Investigators: J. Ahmad, B. Andnakos, F. Arnold, B. Berk, A. Butt, M. Bonacini, N. Bzowej, K. Chopra, E. DeJesus, E. Doo, S. Foti, F. Francis, P. Gironda, R. Gish, A. Gunnison, A. Huang, A. Lippello, S. Mawhinney, L. McDonald, T. Mehmood, R. Nakamatsu, R. Ortiz, M. Rabinovitz, J. Ramirez, A. Shakil, T. Shaw-Stiffel, A. Wakil, E. Xia.
Europe/Middle East Investigators: E. Angeli, L. Afonina, J. Arribas, E. Bakowska, D. Bander, A. Barrios Blandino, A. Boron-Kaczmarska, R. Bova, L. Martin-Carbonero, G. Carosi, A. Cargnel, F. Castelli, A. DeBona, R. Esteban, M. Ferret, Y. Fomin, B. Gazzard, Y. Gilleece, R. Giorgi, J. Gonzalez, G. Gubertini, A. Horban, A. Ignatowska, K. Jurczyk, M. Kazakova, G. Korovina, A. Lazzarin, O. Leonova, A. Lorenzo, A. Mainini, V. Meslov, J. Miro, D. Mutimer, M. Nelson, P. Pulik, M. Puoti, M. Pynka, E. Quiros, N. Qurishi, E. Ribera, J. Rockstroh, V. Soriano, O. Sued, C. Thomas, C. Uberti, A. Valdes, E. Vinogradova, M. Vogel, E. Voigt, E. Voronin, A. Wnuk, S. Zaltron, N. Zaukarova.
BMS Team: G. Bafort, H. Brett-Smith, A. Canzio, R. Colonno J. Cowler, A. Cross, L. Davidson, S. DeCuyper, M. Dela Cruz, G. Denisky, B. Giannakopoulos, G. Gribkoff, A. Hall, J. Jaworski, K. Klesczewski, E. Ledesma, S. Maledrie, R. Petri, R. Rossi, E. Saliba, P. Slade, A. Slocum, M. Whelden, R. Wilber, L. Wilhelm, J. Yang, N. Zimova.
Potential conflicts of interest: M.G.P. has no potential conflicts of interest. B.G. received lecturing fees and ad hoc advise fees from Bristol-Myers Squibb. A.H. received fees from Bristol-Myers Squibb, Merck, and Johnson & Johnson. C.E.B.-M. has no potential conflicts of interest. I.C. has participated in different lectures sponsored by Jansen, Abbott, and Glaxo. M.C.M.-C. has no potential conflicts of interest. V.S. has no potential conflicts of interest. P.P. was an employee of Bristol-Myers Squibb at the time of the study. A.H. is a full-time employee of Bristol-Myers Squibb Company Research and Development. H.B.-S. is a full-time employee of Bristol-Myers Squibb Company Research and Development.
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