ObjectivesTo examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 ...November 2020.DesignObservational cohort study.SettingCOVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA.ParticipantsThere were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort.Primary and secondary outcome measuresIncident acute clinical outcomes, including in-hospital all-cause mortality.ResultsRespectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50– 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by −0.036 per month (95% CI −0.042 to –0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI −0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were −0.024 (95% CI −0.032 to –0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort.ConclusionThe incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.
Background Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to ...predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results. Study Design We used a retrospective cohort study design. Setting & Participants Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period. Predictor EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period. Outcome All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics. Results 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio HR, 1.31 per log unit increase; 95% confidence interval CI, 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively. Limitations This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable. Conclusions The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies.
Background. Persistent infection with human papillomavirus (HPV) is associated with the development and progression of HPV-related disease, including cervical intraepithelial neoplasia (CIN) and ...invasive cervical cancer. Methods. We examined the impact of human immunodeficiency virus (HIV) status and type on the clearance of HPV infection among 614 Senegalese women enrolled in a longitudinal study of HPV and CIN. Women were examined every 4 months for HPV DNA. Clearance was defined as 2 consecutive negative HPV DNA test results. Results. Cox proportional hazard regression with time-dependent covariates indicated that HIV-positive women were less likely to clear HPV infection (adjusted hazard ratio HR, 0.31 95% confidence interval {CI}, 0.21–0.45) than HIV-negative women. Among HIV-positive women, those with CD4 cell counts <200 or from 200 to 500 cells/µL showed a 71% (adjusted HR, 0.29 95% CI, 0.11–0.76) and 32% (adjusted HR, 0.68 95% CI, 0.31–1.48) reduction in the likelihood of HPV clearance, respectively, compared with those with CD4 cell counts >500 cells/µL. HIV-2 infection was associated with an increased likelihood of HPV clearance (adjusted HR, 2.46 95% CI, 1.17–5.16), compared with that for HIV-1 infection. Conclusions. HIV infection reduces the likelihood of HPV clearance. Among HIV-positive women, immunosuppression, as measured by CD4 cell count, reduces the likelihood of HPV clearance, and HIV type appears to be associated with HPV clearance.
The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for ...cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case–control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from β-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio=4.0, confidence interval=1.3–12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV β-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.
Background: DNA methylation changes are an early event in carcinogenesis and are often present in the precursor lesions of various cancers. We examined whether DNA methylation changes might be used ...as markers of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC). Methods: We used methylation-specific polymerase chain reaction (PCR) to analyze promoter hypermethylation of 20 genes, selected on the basis of their role in cervical cancer, in 319 exfoliated cell samples and matched tissue biopsy specimens collected during two studies of Senegalese women with increasingly severe CIN and ICC (histology negative/atypical squamous cells of undetermined significance ASCUS = 142, CIN-1 = 39, CIN-2 = 23, CIN-3/carcinoma in situ CIS = 23, ICC = 92). Logic regression was used to determine the best set of candidate genes to use as disease markers. All statistical tests were two-sided. Results: Similar promoter methylation patterns were seen in genes from exfoliated cell samples and corresponding biopsy specimens. For four genes (CDH13, DAPK1, RARB, and TWIST1), the frequency of hypermethylation increased statistically significantly with increasing severity of neoplasia present in the cervical biopsy (P<.001 for each). By using logic regression, we determined that the best panel of hypermethylated genes included DAPK1, RARB, or TWIST1. At least one of the three genes was hypermethylated in 57% of samples with CIN-3/CIS and in 74% of samples with ICC but in only 5% of samples with CIN-1 or less. The estimated specificity of the three-gene panel was 95%, and its sensitivity was 74% (95% confidence interval CI = 73% to 75%) for ICC and 52% (95% CI = 49% to 55%) for CIN-3/CIS. By extrapolation, we estimated that, among Senegalese women presenting to community-based clinics, detection of the DAPK1, RARB, or TWIST1 hypermethylated gene would reveal histologically confirmed CIN-3 or worse with a sensitivity of 60% (95% CI = 57% to 63%) and a specificity of 95% (95% CI = 94% to 95%). Conclusions: Aberrant promoter methylation analysis on exfoliated cell samples is a potential diagnostic tool for cervical cancer screening that potentially may be used alone or in conjunction with cytology and/or human papillomavirus testing.
To assess the risk of prevalent high-grade cervical squamous intraepithelial lesions (HSILs) or invasive cervical cancer (ICC) associated with human immunodeficiency virus (HIV) type 1, HIV-2, and ...human papillomavirus (HPV) infections, HIV load, and CD4 cell count, we studied 4119 women attending an outpatient clinic in Senegal. HIV infection was associated with increased rates of cervical infection with high-risk HPVs. Among women infected with high-risk HPVs, those with HIV-1 (odds ratio OR, 2.2; 95% confidence interval CI, 1.0–4.8), HIV-2 (OR, 6.0; 95% CI, 2.1–17.1), or dual HIV infection (OR, 8.0; 95% CI, 2.0–31.5) were more likely to have HSILs or ICC diagnosed than were HIV-negative women; this association was not observed among women not infected with high-risk HPVs. Among women with HIV, higher HIV plasma RNA loads and lower CD4 cell counts were associated with high-risk HPV infection and degree of cervical abnormality. Furthermore, HIV-2–positive women were more likely to have HSILs (OR, 3.3; 95% CI, 0.9–12.4) or ICC (OR, 7.9; 95% CI, 1.1–57) than were HIV-1–positive women
On June 23, 2020, Prolia
®
(denosumab) was approved by the National Medical Products Administration (NMPA) in the People’s Republic of China as the first monoclonal antibody for the treatment of ...postmenopausal women with osteoporosis at high risk of fractures. Its brand name in Chinese is 普罗力, a transliteration from the English name “Prolia”, which has an implied meaning of “to give strength to everyone”— a suitable name for a potent anti-resorptive therapy. The approval was supported by a novel marketing authorization application (MAA) that included data from Prolia’s global clinical trial program establishing favorable efficacy and safety, augmented by results from a real-world evidence (RWE) study confirming the effectiveness and safety of Prolia in clinical practice within Taiwan and Hong Kong. Key constructs for this registration-quality RWE study included the fit-for-purpose assessment of data quality, methodology and quantitative assessment of potential biases, good practices of study conduct, and reproducibility of results. Using data from clinical practice in Taiwan and Hong Kong to evaluate the benefits versus risks of Prolia treatment in ethnic Chinese women with postmenopausal osteoporosis, the RWE study results for effectiveness were comparable to efficacy demonstrated in the global clinical trial program and results for safety were consistent with the incidence observed in global post-marketing safety studies. While RWE is often used to monitor postmarket safety of drug products, support health insurance coverage decisions, and inform clinicians on real-world use of medicines, it has not been widely used to support regulatory approval for new medicines in lieu of clinical bridging studies in countries where such studies are required. Well-conducted registrational RWE studies can play a pivotal role in complementing the totality of evidence presented in an MAA. The benefits of such an approach include avoiding the collection of additional placebo-controlled trial data in populations where adequate ethnic characterization of efficacy, effectiveness, and safety may already exist from postmarketing sources, and accelerate access for patients to innovative medicines in important regions. Here, we describe a regulatory case study of a novel MAA incorporating RWE that provided important evidence to confirm the benefit:risk of a new drug and facilitated a label expansion to a new patient population.
The mortality risk associated with attempting to raise hemoglobin (Hb) levels by increasing Epoetin alfa (EPO) doses in hemodialysis patients with persistently low Hb remains poorly understood. ...Design, setting, participants, & measurements. We included hemodialysis patients from a large dialysis provider between July 2000 and June 2001 who had EPO dose and Hb data for 6 consecutive months, and a mean Hb <11 g/dl in months 4 to 6 (sub-11 period). We identify predictors of EPO dose changes during the sub-11 period; evaluate the proportion of patients achieving a Hb >or=11 g/dl after the sub-11 period by dose-change categories; and evaluate the association between EPO dose changes and mortality risk.
Patients were more likely to receive greater EPO dose increases if they had lower EPO doses, higher Hb levels, or were recently hospitalized. Greater EPO dose increases elevated the likelihood of achieving an Hb >or=11 g/dl in the subsequent 3 mo. Larger EPO dose changes over the sub-11 period were not associated with an elevated mortality risk, but having an Hb <9 g/dl at the end of that period independent of dose change was associated with mortality risk. We found that patients receiving larger dose changes and whose resulting Hb level remained <9.5 g/dl at the end of the 3 mo were at elevated mortality risk.
In patients with persistently low Hb levels, mortality risk was strongly associated with the patient's ability to achieve a hematopoietic response rather than the magnitude of EPO dose titrations.
Purpose
Evaluate changes in use of erythropoiesis‐stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and ...reimbursement actions.
Methods
Calendar year patient cohorts (2005‐2013) with breast, colorectal, lung, multiple myeloma, non‐Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011‐2014) were examined to assess hemoglobin levels at ESA initiation.
Results
Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non‐Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs.
Conclusion
Subsequent to important regulatory and reimbursement ESA‐related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling.
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