Antiretroviral therapy and liver disorders in the OPERA® cohort.

INTRODUCTION: A comprehensive assessment of liver disorders was conducted among people living with HIV (PLWH) on a new antiretroviral regimen based on common core agents. METHODS: Treatment-naïve and experienced PLWH first initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) in the OPERA® cohort were included if they had ⩾1 liver chemistry test performed both within 12 months before regimen start and over follow-up. Liver disorders were defined as a diagnosis of drug-induced liver injury (DILI) or moderate/severe liver chemistry elevations (LCE). History of liver disorders experienced within 12 months of initiation was summarized. Liver disorders occurring during follow-up were described as prevalent (all disorders) or incident (disorders occurring among PLWH without a history of liver disorders or advanced liver fibrosis). RESULTS: Out of 16,024 PLWH, 38% initiated DTG, 43% EVG, 5% RAL, and 14% DRV. EVG users were younger and had a lower likelihood of comorbidities or lipid-lowering agent use than DTG users. EVG users were significantly less likely to have a history of moderate/severe LCE or to have prevalent moderate LCE. RAL users were older and had a higher likelihood of comorbidities or lipid-lowering agent use than DTG users. RAL users were significantly more likely to have a history of advanced liver fibrosis and prevalent moderate/severe LCE during follow-up. DRV users were older and had a lower likelihood of lipid-lowering agent use than DTG users. There was no difference in history of LCE, nor in prevalent or incident LCE between DRV and DTG users. No DILI diagnoses were recorded. Discontinuation following a liver disorder was rare (<1%) across all groups. CONCLUSION: While PLWH with comorbidities may have been channeled away from EVG and toward DTG and RAL, the incidence of moderate/severe LCE did not differ between DTG and EVG, RAL, and DRV. PLAIN LANGUAGE SUMMARY: Liver disorders and HIV treatment A comprehensive assessment of liver disorders was conducted using data from the OPERA® cohort, which provides anonymous patient-level clinical data from electronic health records. People living with HIV (PLWH) who were starting a new HIV treatment regimen that included one of four common HIV drugs were included in this study. Liver disorders included drug-induced liver injury (DILI) and moderate or severe liver chemistry elevations. History of a disorder was defined as liver disorders that occurred before starting the new treatment. Prevalent disorders were those that occurred after starting the new treatment in the whole population. Incident disorders were those that occurred after starting the new treatment, but only among PLWH without any history of liver disorders.Out of 16,024 PLWH, 38% initiated dolutegravir (DTG), 43% elvitegravir (EVG), 5% raltegravir (RAL), and 14% darunavir (DRV). EVG users were younger and less likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also less likely to have a history of moderate/severe liver chemistry elevations or to have prevalent moderate liver chemistry elevations. RAL users were older and more likely to have other diseases or use cholesterol lowering drugs compared to DTG users. They were also more likely to have prevalent moderate/severe liver chemistry elevations than DTG users. DRV users were older and less likely to use cholesterol lowering agents compared to DTG users. There was no difference in history of liver chemistry elevations, or in prevalent, or incident liver chemistry elevations between DRV and DTG users. There were no DILI diagnoses and discontinuation of treatment following liver disorders was rare across all groups. Overall, the incidence of liver disorders after starting a new HIV treatment regimen did not differ between four common antiretroviral drugs.

Automated method for detecting increases in frequency of spontaneous adverse event reports over time.

A statistical methodology--focused on temporal change detection--was developed to highlight excursions from baseline spontaneous adverse event (AE) reporting. We used regression (both smooth trend and seasonal components) to model the time course of a drug's reports containing an AE, and then compared the sum of counts in the past 2 months with the fitted trend. The signaling threshold was tuned, using retrospective analysis, to yield acceptable sensitivity and specificity. The method may enhance pharmacovigilance by providing effective automated alerting of reporting aberrations when databases are small, when drugs have established safety profiles, and/or when product quality issues are of concern.

Developing tools for the safety specification in risk management plans: lessons learned from a pilot project.

PURPOSE: Following the adoption of the ICH E2E guideline, risk management plans (RMP) defining the cumulative safety experience and identifying limitations in safety information are now required for marketing authorisation applications (MAA). A collaborative research project was conducted to gain experience with tools for presenting and evaluating data in the safety specification. This paper presents those tools found to be useful and the lessons learned from their use. METHODS: Archive data from a successful MAA were utilised. Methods were assessed for demonstrating the extent of clinical safety experience, evaluating the sensitivity of the clinical trial data to detect treatment differences and identifying safety signals from adverse event and laboratory data to define the extent of safety knowledge with the drug. RESULTS: The extent of clinical safety experience was demonstrated by plots of patient exposure over time. Adverse event data were presented using dot plots, which display the percentages of patients with the events of interest, the odds ratio, and 95% confidence interval. Power and confidence interval plots were utilised for evaluating the sensitivity of the clinical database to detect treatment differences. Box and whisker plots were used to display laboratory data. CONCLUSIONS: This project enabled us to identify new evidence-based methods for presenting and evaluating clinical safety data. These methods represent an advance in the way safety data from clinical trials can be analysed and presented. This project emphasises the importance of early and comprehensive planning of the safety package, including evaluation of the use of epidemiology data.

Patterns of comorbidities in newly diagnosed COPD and asthma in primary care.

STUDY OBJECTIVES: There is increasing interest in the frequency and nature of comorbidities in patients with obstructive lung disease: COPD and asthma. We aimed to quantify baseline rates of comorbidities in COPD and asthma patients and to compare the risks to the general population. DESIGN, SETTING, AND PARTICIPANTS: Within the UK General Practice Research Database, we compared incident patients with COPD (n = 2,699) and asthma (n = 7,931) physician diagnosed in 1998 with age, gender, time, and practice-matched cohorts. Rates were calculated and relative risks (RRs) were estimated for comorbidities in major organ systems and selected medical events of a priori interest. MEASUREMENTS AND RESULTS: In both COPD and asthma, the total sum of diagnoses related to major organ systems was higher than in their matched population controls. Among incident COPD patients, a frequency > 1% within the first year after diagnosis was observed for angina, cataracts, bone fractures, osteoporosis, pneumonia, and respiratory infections, the highest being angina with 4.0%. Compared to the non-COPD cohort, COPD patients were at increased risk for pneumonia (relative risk [RR] = 16.0), osteoporosis (RR = 3.1), respiratory infection (RR = 2.2), myocardial infarction (RR = 1.7), angina (RR = 1.7), fractures (RR = 1.6), and glaucoma (RR = 1.3) [all p < 0.05]. Of note, 2.0% of COPD patients had cataracts recorded, but this rate was no different than that of the non-COPD cohort (RR = 0.9). Among incident asthma patients, the occurrence of events was generally lower, likely due to the younger age distribution, except for 4.0% with respiratory infection (RR = 1.84) and 1.7% with fractures (RR = 1.5). Angina prevalence was 0.7% in the asthma cohort and 1.4 times more common than in patients without asthma. CONCLUSION: COPD and asthma are conditions associated with many comorbidities, albeit asthma to a lesser extent than COPD, which had not been systematically reviewed before. Baseline rates of cardiovascular-, bone-, and other smoking-related conditions are high.