Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

Background: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15–1·22] in men and 1·10 [1·06–1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval −0·84 g/L [95% CI −0·99 to −0·70] in men and −0·45 g/L [–0·59 to −0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval −6·5% [95% CI −7·6 to −5·5] in men and −5·3% [–6·5 to −4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001). Interpretation: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. Funding: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Two-years persistence of anal high-risk HPV infections in women living with HIV, results from the EVVA study

Background: Women living with HIV are at increased risk of anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer because of higher persistence of high-risk HPV (HR-HPV) infection. This study describes the persistence of type-specific anal HR-HPV over two years. Methods: EVVA (Evaluation of HPV, HIV, and AIN in women) is a cohort study of 151 adult women living with HIV in Montreal (Canada), with biannual cervical/anal HPV testing and cytology for 2 years and at two systematic high-resolution anoscopies for all participants. Only participants who completed 2 study visits were included in this analysis (n=135). Results: Persistent anal infection by at least one HR-HPV was observed in 40.7% of participants (55/135, 95% confidence interval (CI) 32.4–49.5), persisting for 2 years in majority. Persistent HPV-16 was observed in 10.4% (14/135, 95%CI 5.8–16.8), detected for 2 years in 13 women. HPV-18 persisted in 6.7% (95%CI 3.1–12.3), HPV-45 in 11.1% (95%CI 6.4–17.7), HPV-51 in 11.9% (95%CI 6.9–18.5), HPV-52 in 8.9% (95%CI 4.7–15.0) and HPV-58 in 7.4% (95%CI 3.6–13.2). Anal histological HSIL was detected in 50.9% (28/55, 95%CI 37.1–64.6) of women with persistent HR-HPV infection by at least one type, and in 15.0% (12/80, 95%CI 8.0–24.7) of women who never had. Conclusions: Our study confirms that persistence of anal HR-HPV is common in women living with HIV, most of the persistent infections being identified for at least 2 years. Anal HSIL is detected more frequently in women with persistent anal HR-HPV

Elevated IgG4 in patient circulation is associated with the risk of disease progression in melanoma

Emerging evidence suggests pathological and immunoregulatory functions for IgG4 antibodies and IgG4(+) B cells in inflammatory diseases and malignancies. We previously reported that IgG4 antibodies restrict activation of immune effector cell functions and impair humoral responses in melanoma. Here, we investigate IgG4 as a predictor of risk for disease progression in a study of human sera (n = 271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n = 71: 47 melanoma patients; 24 healthy volunteers). IgG4 (IgG4/IgG(total)) serum levels were elevated in melanoma. High relative IgG4 levels negatively correlated with progression-free survival (PFS) and overall survival. In early stage (I–II) disease, serum IgG4 was independently negatively prognostic for progression-free survival, as was elevation of IgG4(+) circulating B cells (CD45(+)CD22(+)CD19(+)CD3(−)CD14(−)). In human tissues (n = 256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) IgG4(+) cell infiltrates were found in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases, suggesting inflammatory conditions that favor IgG4 at the peripheral and local levels. Consistent with emerging evidence for an immunosuppressive role for IgG4, these findings indicate association of elevated IgG4 with disease progression and less favorable clinical outcomes. Characterizing immunoglobulin and other humoral immune profiles in melanoma might identify valuable prognostic tools for patient stratification and in the future lead to more effective treatments less prone to tumor-induced blockade mechanisms

Identifying risk factors for prevalent anal human papillomavirus type 16 infection in women living with HIV.

BackgroundWomen living with HIV (WLHIV) have a high risk of anal cancer. Identifying risk factors for anal HPV 16 infection, the most significant risk factor for anal cancer, is essential for prevention and screening strategies.MethodsIn the EVVA Cohort study, 151 WLHIV had cervical and anal HPV testing with genotyping every 6 months for 2 years, while demographic and clinical data were collected via questionnaires and chart reviews. Here, we present results of baseline data analyzed using multivariable logistic regression.ResultsAmong 150 women with adequate HPV test results at baseline, HPV 16 DNA was detected anally in 23 (15.3%; 95%CI:10.4-22.1) and cervically in 5 (3.3%; 95%CI:1.4-7.8). In multivariable analysis, current smoking (OR = 6.0; 95%CI: 1.5-23.9), nadir CD4 count ≤ 200 cells/μL (OR = 8.4; 95%CI: 2.0-34.3), prevalent cervical HPV 16 (OR = 14.7; 95%CI: 1.0-222.5) and anogenital herpes in previous 6 months (OR = 9.8, 95%CI: 1.7-56.8) were associated with prevalent anal HPV 16.ConclusionsKnowledge of risk factors can help identify WLHIV at greatest risk of anal HPV 16 infection and, potentially, developing subsequent anal cancer. Identification of the subgroup of these women in whom HPV 16 persists could be an early step in the algorithm of anal cancer screening