Clinical characteristics and outcomes of COVID-19 in people living with HIV in Belgium: A multicenter, retrospective cohort.

The aim of this study was to describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among people living with HIV (PLWH) in Belgium. We performed a retrospective multicenter cohort analysis of PLWH with either laboratory-confirmed, radiologically diagnosed, or clinically suspected COVID-19 between February 15, 2020 and May 31, 2020. The primary endpoint was outcome of COVID-19. Secondary endpoints included rate of hospitalization and length of hospital stay and rate of Intensive Care Unit (ICU) admission and mechanical ventilation. One hundred and one patients were included in this study. Patients were categorized as having either laboratory-confirmed (n = 65), radiologically-diagnosed (n = 3), or clinically suspected COVID-19 (n = 33). The median age was 51.3 years (interquartile range [IQR] 41.3-57.3) and 44% were female. Ninety-four percent of patients were virologically suppressed and 67% had a CD4+ cell count more than or equal to 500 cells/µl. Overall, 46% of patients required hospitalization and the median length of hospital stay was 6 days (IQR 3-15). Age more than or equal to 50 years, Black Sub-Saharan African patients, and being on an integrase strand transfer inhibitor-based regimen were associated with being hospitalized. ICU admission and mechanical ventilation was required for 15% and 10% of all patients respectively. Overall, 9% of patients died while 78 (77%) patients made a full recovery. HIV patients with COVID-19 experienced a high degree of hospitalization despite having elevated CD4+ cell counts and a high rate of virologic suppression. Matched case-control studies are warranted to measure the impact that HIV may have on patients with COVID-19.

Seroprevalence of Antibodies against Diphtheria, Tetanus and Pertussis in Adult At-Risk Patients.

Patients with chronic diseases are at increased risk of complications following infection. It remains, however, unknown to what extend they are protected against vaccine-preventable diseases. We assessed seroprevalence of antibodies against diphtheria, tetanus and pertussis to evaluate whether current vaccination programs in Belgium are adequate. Antibody titers were assessed with a bead-based multiplex assay in serum of 1052 adults with chronic diseases. We included patients with diabetes mellitus type 1 (DM1) (n = 172), DM2 (n = 77), chronic kidney disease (n = 130), chronic obstructive pulmonary disease (COPD) (n = 170), heart failure (n = 77), HIV (n = 196) and solid organ transplant (SOT) recipients (n = 230). Factors associated with seroprevalence were analysed with multiple logistic regression. We found seroprotective titers in 29% for diphtheria (≥0.1 IU/mL), in 83% for tetanus (≥0.1 IU/mL) and 22% had antibodies against pertussis (≥5 IU/mL). Seroprotection rates were higher (p < 0.001) when vaccinated within the last ten years. Furthermore, diphtheria seroprotection decreased with age (p < 0.001). Tetanus seroprotection was less reached in women (p < 0.001) and older age groups (p < 0.001). For pertussis, women had more often a titer suggestive of a recent infection or vaccination (≥100 IU/mL, p < 0.01). We conclude that except for tetanus, the vast majority of at-risk patients remains susceptible to vaccine-preventable diseases such as diphtheria and pertussis.

Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV).

BACKGROUND: The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant. METHODS: This is a phase III investigator-initiated study in 100 persons living with HIV (age 18-45 years) and 171 SOT recipients (age 18-55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs). RESULTS: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study. CONCLUSIONS: Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.

Vaccination coverage of recommended vaccines and determinants of vaccination in at-risk groups.

Upon exposure to vaccine-preventable diseases, certain individuals are at increased risk for complications due to preexisting diseases, age or immunosuppressive treatment. Vaccination against influenza, pneumococcal disease and hepatitis B (for some groups) is advised in addition to standard vaccination against diphtheria, tetanus and pertussis. We estimated the vaccination coverage and determinants of recommended vaccinations in patients with diabetes mellitus type 1 (n = 173) and type 2 (n = 177), chronic kidney disease (CKD) (n = 138), heart failure (n = 200), chronic obstructive pulmonary disease (COPD) (n = 187), HIV (n = 201) or solid organ transplantation (SOT) (n = 201) in a monocentric study. Vaccination data were retrieved from documents provided by patients and general practitioners, and from the Flemish vaccination register. Less than 10% had received all recommended vaccines. Overall, 29% of subjects were vaccinated against diphtheria-tetanus, 10% against pertussis, 44% against influenza, 32% against pneumococcal disease and 24% of HIV patients and 31% of CKD patients against hepatitis B. Age was positively associated with vaccination against influenza (OR:2.0, p < .01) and pneumococcal disease (OR:2.6, p < .001). Patients with COPD, HIV and SOT were more likely to be vaccinated against influenza (OR:2.8, p < .001, OR:1.8, p < .05; OR:2.0, p < .001, respectively) and pneumococcal disease (OR:2.9, p < .001, OR:25.0, p < .001; OR:2.6, p < .001, respectively) than patients with heart failure. Reason for non-vaccination were concerns about effectiveness, necessity and side effects of influenza vaccines, and not being aware of the recommendation for pneumococcal disease. Initiatives to monitor the vaccination status of vulnerable patients are needed, which is why we advocate systematic vaccination registration and frequent communication about vaccination.

Efficacy and safety of a Belgian tertiary care outpatient parenteral antimicrobial therapy (OPAT) program.

PURPOSE: Evidence supports the implementation of outpatient parenteral antimicrobial therapy (OPAT) as standard of care. Until 2015 the overall experience with OPAT in Belgium remained limited. The aim of this study was to evaluate the efficacy and safety of a Belgian 'OPAT at home' program, which was implemented in University Hospitals Leuven starting from January 2017. METHODS: A mono-centric, prospective, observational study was carried out. All OPAT cases discharged between 10 January 2017 and 10 January 2019 were included in the study. Relevant demographic and clinical patient data were collected. The outcomes were clinical cure rate, OPAT related readmission rate, adverse event rate and patients' satisfaction. RESULTS: Over the two-year study period, 152 OPAT episodes were started in 130 patients, resulting in 3153 avoided hospitalization days which corresponds to 5.4 freed hospital beds. Urinary tract infections accounted for 40.8% of OPAT courses and temocillin was the most frequently used antibiotic (24.3%). Cure was achieved in 97.9% of the OPAT episodes. During 22 (14.5%) OPAT episodes, patients experienced adverse events, including line related adverse events (7.9%) and adverse drug events (6.6%). An OPAT related readmission rate of 9.2% was observed, mostly related to line-associated adverse events. All patients who completed the satisfaction survey (n = 23) were very satisfied with their OPAT course. CONCLUSION: The University Hospitals Leuven OPAT program is associated with a high level of clinical cure and low all-cause readmission and adverse event rates. Improvement actions are described to further reduce the readmission rate to less than 5.0%.

Conservative treatment of non-aneurysmal infectious aortitis: a case report and review of the literature.

BACKGROUND:  Non-aneurysmal infectious aortitis is a rare clinical entity with most often lethal complications when surgical intervention is delayed. OBJECTIVES:  This report describes the case of a non-aneurysmal infectious aortitis complicated with a penetrating aortic ulcer in an elderly woman, caused by a methicillin-sensitive Staphylococcus aureus. Surgery was deemed contra-indicated and treatment was limited to the administration of intravenous vancomycin (2 grams daily), followed by flucloxacillin (6 times 2 grams daily). She remains well after one year. METHODS: The Internet databases Medline and Embase were searched. Articles were selected based on relevanceof abstract, article type and impact of the journal. RESULTS:  A literature review addresses current insights in the pathogenesis, diagnosis, and treatment of non-aneurysmal infectious aortitis.

Outpatient parenteral antimicrobial therapy and antibiotic stewardship: opponents or teammates?

PURPOSE: This narrative review aims to describe barriers of outpatient parenteral antimicrobial therapy at home (OPAT), potentially compromising general standards of antibiotic stewardship (ABS) and facilitators of OPAT for ABS. METHODS: After a literature review, five authors determined the barriers and facilitators to discuss in this review. RESULTS: Sixty-six publications were included in the narrative review and seven barriers and five facilitators are discussed in this article. The impracticability of multiple daily dosing during OPAT, the impact of real-life temperature variations, deviations of the infusion rates of elastomeric devices, access to prolonged intravenous antibiotic therapy, not administering loading doses before the initiation of extended or continuous infusions and the transmural nature of care associated with OPAT, can lead to deviations of recommended treatment regimens and sub-optimal clinical and laboratory follow-up, with a risk of inferior clinical outcomes, adverse events, drug-resistance and higher costs. On the other hand, OPAT provides access to treatments with intravenous antibiotics and simultaneously avoids prolonged hospitalization. CONCLUSION: Implementing ABS guidelines in OPAT programs, e.g., by using a multidisciplinary team approach and facility-specific protocols for OPAT with patient selection criteria and instructions for selection, storage, preparation and administration of antibiotics, can improve appropriate antibiotic use. Additionally, further research should examine the effectiveness of these interventions on outcomes of OPAT.

Belgian guidelines for non-occupational HIV post-exposure prophylaxis 2017.

We present the updated Belgian guidelines for the use of non-occupational HIV post-exposure prophylaxis (NONOPEP). This document is inspired by UK guidelines 2015, adapted to the Belgian situation and approved by all AIDS reference centers in Belgium. When recommended, NONOPEP should be initiated as soon as possible, preferably within 24 h of exposure but can be offered up to 72 h. The duration of NONOPEP should be 28 days. These current guidelines include epidemiologic estimations, which can be used to calculate the risk of infection after a potential exposure and help to decide whether or not to start prophylaxis. We review which medications to use in the context of the last Belgian NONOPEP convention, provide a checklist for initial assessment, and make recommendations for monitoring individuals receiving NONOPEP.

Fifth Percentile Cutoff Values for Antipneumococcal Polysaccharide and Anti-Salmonella typhi Vi IgG Describe a Normal Polysaccharide Response.

BACKGROUND: Serotype-specific antibody responses to unconjugated pneumococcal polysaccharide vaccine (PPV) evaluated by a World Health Organization (WHO)-standardized enzyme-linked immunosorbent assay (ELISA) are the gold standard for diagnosis of specific polysaccharide antibody deficiency (SAD). The American Academy of Allergy, Asthma and Immunology (AAAAI) has proposed guidelines to interpret the PPV response measured by ELISA, but these are based on limited evidence. Additionally, ELISA is costly and labor-intensive. Measurement of antibody response to Salmonella typhi (S. typhi) Vi vaccine and serum allohemagglutinins (AHA) have been suggested as alternatives. However, there are no large cohort studies and cutoff values are lacking. OBJECTIVE: To establish cutoff values for antipneumococcal polysaccharide antibody response, anti-S. typhi Vi antibody, and AHA. METHODS: One hundred healthy subjects (10-55 years) were vaccinated with PPV and S. typhi Vi vaccine. Blood samples were obtained prior to and 3-4 weeks after vaccination. Polysaccharide responses to 3 serotypes were measured by WHO ELISA and to 12 serotypes by an in-house bead-based multiplex assay. Anti-S. typhi Vi IgG were measured with a commercial ELISA kit. AHA were measured by agglutination method. RESULTS: Applying AAAAI criteria, 30% of healthy subjects had a SAD. Using serotype-specific fifth percentile (p5) cutoff values for postvaccination IgG and fold increase pre- over postvaccination, only 4% of subjects had SAD. One-sided 95% prediction intervals for anti-S. typhi Vi postvaccination IgG (≥11.2 U/ml) and fold increase (≥2) were established. Eight percent had a response to S. typhi Vi vaccine below these cutoffs. AHA titer p5 cutoffs were ½ for anti-B and » for anti-A. CONCLUSION: We establish reference cutoff values for interpretation of PPV response measured by bead-based assay, cutoff values for S. typhi Vi vaccine responses, and normal values for AHA. For the first time, the intraindividual consistency of all three methods is studied in a large cohort.

More Than Meets the Eye: Klebsiella pneumoniae Invasive Liver Abscess Syndrome Presenting with Endophthalmitis.

BACKGROUND: Endophthalmitis is a feared complication of pyogenic liver abscesses caused by hypervirulent Klebsiella pneumoniae strains. First described in East Asia in the 1980s, this invasive syndrome is only recently emerging in Europe and America. CASE REPORT: We describe an 84-year-old man who presented to the emergency department with fever, orbital cellulitis, and bilateral visual loss. Although the patient had no overt abdominal symptoms, computed tomography scan revealed a pyogenic liver abscess. Blood cultures were positive for K. pneumoniae. Initial treatment consisted of intravenous ceftriaxone and intravitreal ceftazidime. A unilateral vitrectomy was performed. The patient survived with severe visual sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: K. pneumoniae pyogenic liver abscess with metastatic endophthalmitis is a relatively new syndrome that should be considered in patients presenting with acute vision loss who appear septic, with or without abdominal complaints. Early recognition prohibits delays in lifesaving treatment.

Case report of a false positive result of the Xpert® MTB/RIF assay for rifampicin resistance in Mycobacterium tuberculosis complex.

In the present case, we report a false positive result for the detection of rifampicin (RIF) resistance by the Xpert® MTB/RIF assay, version G4.Miliary Mycobacterium tuberculosis infection (miliary TB) was suspected in a 50-year old Angolan woman. Imaging of the thorax and abdomen displayed diffuse lesions. The Xpert® MTB/RIF assay conducted on the broncho-alveolar lavage (BAL) fluid was positive for TB and positive for RIF resistance. Confirmatory molecular tests and the phenotypic drug susceptibility determination supported the diagnosis of TB but not RIF resistance. The patient was treated successfully with a conventional therapeutic scheme. Because, the Xpert® MTB/RIF assay allows the simultaneous detection of TB and RIF resistance, the World Health Organisation (WHO) recommends its use as initial diagnostic test, over microscopy, culture and phenotypic drug susceptibility testing. Even though specificity of the Xpert® MTB/RIF assay version G4 is high, false positive test results remain possible and have to be considered for the interpretation of the RIF resistance detection by Xpert® MTB/RIF assay.

Incidence and risk factors of fever in a contemporary cohort of HIV-patients with good access to antiretroviral therapy.

OBJECTIVE: To study incidence and to determine risk factors of fever in a contemporary cohort of HIV-infected patients with access to antiretroviral therapy. METHODS: Prospective study in a cohort of HIV-infected patients in Belgium from 2009 to 2013. RESULTS: 759 patients were followed for a total of 2136 patient years. The incidence of fever was low, with an incidence rate of 0.103 (95% CI 0.078; 0.135) febrile episodes per patient per year for temperature 38.3 °C or higher measured by a health care provider. Gender, age, ethnicity, and calendar year of measurement were no significant risk factors for fever in univariable analysis, but recent HIV diagnosis, prior AIDS, nadir CD4 cell count, last CD4 cell count, and viral load were, as were use of antiretroviral therapy, recent start of antiretroviral therapy and recent switch of antiretroviral therapy. Recent stop of antiretroviral therapy was no significant risk factor. In multivariable analysis prior AIDS, last CD4 and viral load remained significant risk factors, but use of antiretroviral therapy not. CONCLUSION: In this contemporary cohort, incidence of fever was low but CD4 cell count less than 200/mm³ remained associated with the highest incidence of fever.

Clinical presentation, causes and outcome of febrile episodes in a prospective cohort of HIV-infected patients.

BACKGROUND: Fever was frequently caused by opportunistic conditions in HIV-patients in the early years of the epidemic. Little is known about diagnostic spectrum and outcome of febrile episodes in patients with good access to antiretroviral therapy. METHODS: We prospectively studied clinical presentation, diagnosis and outcome of febrile episodes in a contemporary cohort of HIV-patients with good access to antiretroviral therapy. Fever was defined as temperature 38.3 °C or higher, measured by a health care provider. RESULTS: We found 220 febrile episodes in 146 patients. In 25.9% of episodes the patient had a CD4 less than 200/mm³ and in 78.6% the patient was on antiretroviral therapy. There were multiple episodes in 44 patients. A diagnosis was established in 91.8%. Infection accounted for 82.3%, mainly respiratory tract infections, viral syndromes and abdominal infections. Malignancy, drug reactions and inflammatory conditions accounted together for less than 12% of episodes. Fifteen percent were attributed to opportunistic conditions. Episodes in patients with CD4 less than 200 were less likely to be caused by infection, but more likely to be caused by malignancy, drug reactions and opportunistic conditions. In 6.4% the patient died within six months after the onset of fever. Risk factors for death at six months in multivariable analysis were higher age and lower CD4. CONCLUSIONS: HIV-patients with access to antiretroviral therapy present with fever mostly due to conditions common in the general population. HIV-patients with low CD4 remain at risk for fever due to opportunistic conditions and death.

Cladophialophora bantiana osteomyelitis in a renal transplant patient.

Cladophialophora bantiana is a neurotropic dematiaceous fungus which rarely causes disseminated disease. We report a case of proven C. bantiana osteomyelitis in a renal transplant recipient, complicated with probable cerebral disease. Stable disease was reached after combined antifungal therapies, immune enhancement and amputation of the infected lower limb.

Characteristics, causes, and outcome of 54 episodes of bloodstream infections in a cohort of HIV patients.

BACKGROUND: Patients infected with human immunodeficiency virus (HIV) have an increased risk for bloodstream infections (BSIs). Published recent data on characteristics, etiology, and outcome of BSIs in HIV patients in high income countries are scarce. METHODS: Blood cultures from 2001 to 2011 from adult HIV patients were retrieved. Blood cultures considered to be contamination based on isolates and clinical context were excluded. Clinical and microbiological characteristics of BSIs and patients were described, those of community-acquired and nosocomial episodes were compared, and risk factors for 6-month mortality were analyzed. RESULTS: We found 54 episodes of true BSI in 46 patients. Demographics were similar to those of the source cohort of all patients followed between 2001 and 2011. In 63% there was prior AIDS, in 91% a CD4 nadir below 200/mm(3), and in 72% a latest CD4 count < 200/mm(3). In 13% of patients BSI preceded a new HIV diagnosis within 1 week. Main causative microorganisms were coagulase-negative staphylococci (26%), Streptococcus pneumoniae (20%), and Enterococcus spp. (13%). The most frequent diagnoses were pneumonia (28%) and catheter-related BSI (CRBSI) (28%); 56% of episodes were nosocomial. The 1-month mortality rate was 17%, with a cause of death apparently unrelated to the BSI in five of nine episodes. The 6-month mortality was 28%. Factors of co-morbidity or immunodeficiency other than HIV were significantly associated with 6-month mortality. CONCLUSIONS: BSIs in HIV-infected patients occur predominantly in patients with advanced HIV infection. Community-acquired bacteremic pneumococcal pneumonia and nosocomial staphylococcal CRBSIs are the main causes. Mortality following BSI is high, and seems to be driven by underlying complicated HIV infection.

Trends and predictors of transmitted drug resistance (TDR) and clusters with TDR in a local Belgian HIV-1 epidemic.

We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7-11.9), 6.5% (CI: 5.0-8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4-3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4-3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures.

The genealogical population dynamics of HIV-1 in a large transmission chain: bridging within and among host evolutionary rates.

Transmission lies at the interface of human immunodeficiency virus type 1 (HIV-1) evolution within and among hosts and separates distinct selective pressures that impose differences in both the mode of diversification and the tempo of evolution. In the absence of comprehensive direct comparative analyses of the evolutionary processes at different biological scales, our understanding of how fast within-host HIV-1 evolutionary rates translate to lower rates at the between host level remains incomplete. Here, we address this by analyzing pol and env data from a large HIV-1 subtype C transmission chain for which both the timing and the direction is known for most transmission events. To this purpose, we develop a new transmission model in a Bayesian genealogical inference framework and demonstrate how to constrain the viral evolutionary history to be compatible with the transmission history while simultaneously inferring the within-host evolutionary and population dynamics. We show that accommodating a transmission bottleneck affords the best fit our data, but the sparse within-host HIV-1 sampling prevents accurate quantification of the concomitant loss in genetic diversity. We draw inference under the transmission model to estimate HIV-1 evolutionary rates among epidemiologically-related patients and demonstrate that they lie in between fast intra-host rates and lower rates among epidemiologically unrelated individuals infected with HIV subtype C. Using a new molecular clock approach, we quantify and find support for a lower evolutionary rate along branches that accommodate a transmission event or branches that represent the entire backbone of transmitted lineages in our transmission history. Finally, we recover the rate differences at the different biological scales for both synonymous and non-synonymous substitution rates, which is only compatible with the 'store and retrieve' hypothesis positing that viruses stored early in latently infected cells preferentially transmit or establish new infections upon reactivation.

In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.