Worldwide post-marketing safety surveillance experience with tofacitinib in ulcerative colitis.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). AIMS: To report an analysis of PMS case safety reports for tofacitinib in patients with UC METHODS: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations. RESULTS: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders. CONCLUSIONS: The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.

Tofacitinib Treatment Safety in Moderate to Severe Ulcerative Colitis: Comparison of Observational Population Cohort Data From the IBM MarketScan® Administrative Claims Database With Tofacitinib Trial Data.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program. METHODS: Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157). RESULTS: Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar. CONCLUSIONS: When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher. CLINICALTRIALS.GOV: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia.

INTRODUCTION: Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease of the colon, characterized by relapsing and remitting symptoms. Although traditionally viewed as a Western disease, the incidence and prevalence of UC is increasing in developing regions, including Asian countries. AREAS COVERED: A PubMed search identified articles describing epidemiology, disease burden, patient demographics, clinical characteristics, risk factors, and treatment of UC across Asia. We review the epidemiology and disease course of UC across Asia, including region-specific factors that may aid development of more cost-effective treatment approaches tailored to the needs of Asian populations. EXPERT OPINION: The opinion of non-Pfizer-affiliated practicing gastroenterologists is that epidemiological data from the last four decades have shown 1.5-fold to almost 20-fold increases in the incidence and prevalence of UC in some Asian countries, although prevalence remains generally lower than in the West. As the prevalence of UC rises, so will overall healthcare costs. Disparities in healthcare systems and funding mean that different Asian countries face unique challenges in how best to use available resources, including selection from a growing number of emerging treatment options. More clinical trial and real-world data are required to help define treatment approaches that will most benefit Asian populations.

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). AIM: To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme. METHODS: DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open-label, long-term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts. RESULTS: 1157 patients (2404 patient-years' exposure; ≤ 6.1 years' tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In maintenance, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient-years; 95% CI]: 0.04 [0.00-0.23]); four had PE (0.16 [0.04-0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC. CONCLUSIONS: In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Validation studies of claims data in the Asia-Pacific region: A comprehensive review.

PURPOSE: To describe published validation studies of administrative health care claims data in the Asia-Pacific region. METHODS: A comprehensive literature search was conducted in PubMed for English language articles published through 31-Oct-2017 in humans from 10 Asian-Pacific countries or regions (Japan, Australia, New Zealand, China, Hong Kong, India, Singapore, South Korea, Taiwan, and Thailand) that validated claims-based diagnoses with a gold standard data source. Search terms included the: validation, validity, accuracy, sensitivity, agreement, specificity, positive predictive value, kappa, kappa coefficient, and Cohen's kappa. RESULTS: Forty-three studies across six countries were identified: Australia (21); Japan (6); South Korea (6); Taiwan (7); Singapore (2); and New Zealand (1). Gold standard diagnoses were obtained from: medical records (18); registry data (11); self-reported questionnaires (5); and other data sources (9). Validity measures used included sensitivity, specificity, positive and negative predictive values (12); sensitivity, specificity, and positive predictive value (4); sensitivity and specificity (4); sensitivity and positive predictive value (4); and combinations of other measures (19). Validated outcomes included medical conditions (28); disease-specific comorbidities (8); death, smoking, and other (ie, injury, hospital outcome measures) (5); medication/transfusion (2). Approximately 72% of the studies were published within the last 5 years. CONCLUSIONS: Validation studies of claims data published in the English language in the Asia-Pacific region are very limited. Given the increased reliance on administrative health care databases for pharmacoepidemiology and the need for ensuring the credibility of results from such data, additional support for the conduct of validation research of claims data in the Asia-Pacific region is needed.

Prenatal exposure to zidovudine and risk for ventricular septal defects and congenital heart defects: data from the Antiretroviral Pregnancy Registry.

OBJECTIVE: To assess the risk for ventricular septal defects and congenital heart defects following zidovudine exposure during pregnancy using data from the Antiretroviral Pregnancy Registry. STUDY DESIGN: Data on 16,304 prospectively reported pregnancies were analyzed to estimate the frequency and risk of ventricular septal defects and congenital heart defects, comparing exposure between zidovudine-containing regimens and non-zidovudine antiretroviral regimens. The numerator includes defect cases in outcomes at ≥ 20 weeks of gestational age. The denominator includes live birth outcomes. Infants with chromosomal anomalies were excluded. RESULTS: There were 15,451 live birth outcomes; 13,073 were prenatally exposed to zidovudine-containing regimens and 2378 to non-zidovudine containing regimens. There were 36 ventricular septal defect cases: 31 exposed to prenatal zidovudine and 5 unexposed. Nine of the zidovudine-exposed cases had earliest exposure in the first trimester; 22 had second/third trimester exposure. Of the 5 ventricular septal defect cases not exposed to zidovudine, 2 had earliest exposure to non-zidovudine antiretroviral regimens in the first trimester, and 3 had exposure in the second/third trimester. The prevalence of ventricular septal defect was 0.24% (95% confidence interval: 0.16, 0.34) for infants exposed to zidovudine-containing regimens and 0.21% (95% confidence interval: 0.07, 0.49) for non-zidovudine regimens. The relative risk comparing the 2 was 1.13 (95% confidence interval: 0.44, 2.90). There were a total of 90 congenital heart defect cases; 78 were exposed prenatally to zidovudine-containing regimens, and 12 were unexposed. Twenty-six of the zidovudine-exposed cases had earliest exposure in the first trimester and 52 had second/third trimester exposure. Six congenital heart defect cases with non-zidovudine antiretroviral regimens had earliest exposure in the first trimester and 6 had exposure in the second/third trimester. The prevalence of congenital heart defects was 0.60% (95% confidence interval: 0.47, 0.74) for infants exposed to zidovudine-containing regimens and 0.50% (95% confidence interval: 0.26, 0.88) for non-zidovudine regimens. The relative risk comparing the 2 was 1.18 (95% confidence interval: 0.64, 2.17). CONCLUSIONS: The prevalence and risk of ventricular septal defects and congenital heart defects among infants exposed to zidovudine-containing regimens is not significantly different from the prevalence and risk in infants exposed to non-zidovudine containing regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01137981.

Abacavir and lamivudine exposures during pregnancy and non-defect adverse pregnancy outcomes: data from the antiretroviral pregnancy registry.

BACKGROUND: The antiretroviral (ARV) pregnancy registry, an international voluntary registry, provides information on teratogenicity and non-defect adverse pregnancy outcomes. METHODS: We analyzed ARV pregnancy registry prospective singleton pregnancies, estimating frequencies of and risk for nondefect adverse outcomes among HIV-infected women. Prenatal exposures to abacavir (ABC)-containing regimens vs. non-ABC ARV regimens, and lamivudine (3TC)-containing regimens vs. non-3TC regimens were compared. RESULTS: Of 2006 outcomes with prenatal ABC exposure, 95.6% were live births; 4.4% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had low birth weight (LBW); 11.9% were preterm births. Relative risks comparing exposure to ABC vs. non-ABC ARV regimens were spontaneous abortions 0.92 [95% confidence interval (CI): 0.66 to 1.27], induced abortions 0.84 (95% CI: 0.59 to 1.21), stillbirths 0.59 (95% CI: 0.35 to 1.00), preterm births 0.96 (95% CI: 0.84 to 1.09), and LBW 1.00 (95% CI: 0.90 to 1.13). Of 11,211 outcomes with prenatal 3TC exposure, 95.3% were live births; 4.7% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had LBW; 11.9% were preterm births. The relative risks comparing exposure to 3TC vs. non-3TC ARV regimens were spontaneous abortions 0.63 (95% CI: 0.50 to 0.80), induced abortions 0.54 (95% CI: 0.43 to 0.69), stillbirths 1.25 (95% CI: 0.86 to 1.80), preterm births 0.86 (95% CI: 0.77 to 0.95), and LBW 1.02 (95% CI: 0.93 to 1.12). CONCLUSIONS: ABC-containing and non-ABC ARV regimens have similar risks for non-birth defect adverse pregnancy outcomes. 3TC-containing regimens have lower risk for spontaneous abortions, induced abortions, and preterm births compared with non-3TC ARV regimens, whereas both regimens had similar prevalence and risks for stillbirths and LBW.

Role of sexual transmission of HIV among young noninjection and injection opiate users: a respondent-driven sampling study.

BACKGROUND: Sexual transmissibility of HIV among young drug users in China has been investigated in few studies. The objective of this study was to examine the role of sexual transmission on HIV infection among injection drug users (IDUs) and noninjection drug users (NIDUs). METHODS: Respondent-driven sampling (RDS) was used to recruit 426 young heroin/opium drug users in Yunnan, China. Logistic regression modeling was performed to examine interrelationships among risky sexual behaviors, drug-use modes, and drug-use practices. RESULTS: Substantial proportions of NIDUs and IDUs reported engagement in risky sexual behaviors including: (1) multiple sexual partners (42% of NIDUs vs. 37% of IDUs), (2) concurrent sexual partnerships (48% vs. 46%), (3) commercial sex partners (23% vs. 24%), and sex partners who were NIDUs (14% vs. 17%). Both NIDUs and IDUs reported low levels of condom use with nonregular partners (48% vs. 42%) and regular partner (24% vs. 27%), and having a history of recent methamphetamine use (21% vs. 18%). Compared to IDUs, NIDUs reported having had fewer sex partners who were IDUs, fewer IDU network peers, more NIDU network peers, and having lower levels of HIV knowledge and self-perceived HIV risk. CONCLUSIONS: Generalization of the HIV epidemic from high-risk groups to the general population may be driven by risky sexual behavior among drug users. Reducing sexual transmission of HIV among both IDUs and NIDUs is the next major challenge for HIV intervention among drug users in China.

Sexual transmissibility of HIV among opiate users with concurrent sexual partnerships: an egocentric network study in Yunnan, China.

AIMS: To investigate the patterns of concurrent sexual partnerships among young opiate users and sexual transmissibility of human immunodeficiency virus (HIV) in concurrent sexual partnerships in drug-use and sexual networks. DESIGN: Cross-sectional design. PARTICIPANTS: A total of 426 young opiate users in Yunnan, China. SETTING: Young opiate users recruited from their network ties. MEASUREMENT: Respondent-driven sampling (RDS) was used to recruit participants. Multiple logistic regressions were performed to analyze the relationships of concurrent sexual partnerships with egocentric social network components, risky sexual behavior for HIV and drug-use practices. FINDINGS: The RDS-adjusted prevalence of concurrent sexual partners was 42.9% among opiate users. Opiate users with concurrent sexual partnerships were more likely to engage in risky HIV-related sexual behavior, compared to those without. Specifically, they were more likely to report having had four or more sexual partners (26.3% versus 2.0%), having had a spouse or boy/girlfriends who also had concurrent sexual partnerships (28.1% versus 8.2%), having exchanged drug for sex (12.4% versus 3.8%), having had sexual partners who were non-injection drug users (22.6% versus 10.1%), having had sexual partners who were injection drug users (25.3% versus 13.5%) and having used club drugs (26.3% versus 13.5%). There were no significant differences in consistent condom use between opiate users with sexual concurrency and those without. The same proportion (25.8%) of opiate users in the two groups reported having consistently used condoms when having sex with regular partners, and 46.3% of opiate users with sexual concurrency and 36.4% of those without such concurrency consistently used condoms with non-regular partners. CONCLUSION: The expansion of the human immunodeficiency virus epidemic from high-risk populations to the general population in China may be driven by concurrent sexual partnerships. Behavioral interventions targeting safer sex should be integrated into harm reduction programmes.

Role of social network dimensions in the transition to injection drug use: actions speak louder than words.

The objective of this study was to examine the influences of social network factors, particularly social support and norms, in the transition from non-injection heroin and/or opiate use to heroin-injection, which is one of the leading causes of the spread of HIV/AIDS in China. Respondent-driven sampling was used to recruit young heroin and/or opiate users in an egocentric network study in Yunnan, China. Multivariate logistic regression using hierarchical combinations of candidate variables was used to analyze network factors for the injection transition. A total of 3,121 social network alters were reported by 403 egos with an average network size of eight. Fifty-eight percent of egos transitioned to heroin-injection from non-injection. This transition was associated with having a larger sex network size, a larger number of heroin injectors in one's network, and a higher network density. The findings enhance our understanding of the influence of social network dimensions on the transition to injection drug use. Accordingly, the development of interventions for heroin and/or opiate users in China should consider social network characteristics.

Nonfoodborne Vibrio infections: an important cause of morbidity and mortality in the United States, 1997-2006.

BACKGROUND: Infections due to Vibrio species cause an estimated 8000 illnesses annually, often through consumption of undercooked seafood. Like foodborne Vibrio infections, nonfoodborne Vibrio infections (NFVI) also result in serious illness, but awareness of these infections is limited. METHODS: We analyzed illnesses occuring during the period 1997-2006 that were reported to the Centers for Disease Control and Prevention's Cholera and Other Vibrio Illness Surveillance system. The diagnosis of NFVI required isolation of Vibrio species from a patient with contact with seawater. RESULTS: Of 4754 Vibrio infections reported, 1210 (25%) were NFVIs. Vibrio vulnificus infections were the most common (accounting for 35% of NFVIs), with 72% of V. vulnificus infections reported from residents of Gulf Coast states. Infections due to V. vulnificus resulted in fever (72% of cases), cellulitis (85%), amputation (10%), and death (17%). V. vulnificus caused 62 NFVI-associated deaths (78%). Recreational activities accounted for 70% of exposures for patients with NFVIs associated with all species. Patients with liver disease were significantly more likely to die as a result of infection (odds ratio, 7.8; 95% confidence interval, 2.8-21.9). Regardless of pre-existing conditions, patients were more likely to die when hospitalization occurred >2 days after symptom onset (odds ratio, 2.9; 95% confidence interval, 1.8-4.8). CONCLUSION: NFVIs, especially those due to V. vulnificus, demonstrate high morbidity and mortality. Persons with liver disease should be advised of the risks associated with seawater exposure if a wound is already present or is likely to occur. Clinicians should consider Vibrio species as an etiologic agent in infections occurring in persons with recent seawater exposure, even if the individual was only exposed during recreational marine activities. Immediate antibiotic treatment with aggressive monitoring is advised in suspected cases.