Extraintestinal Manifestations in Vedolizumab and Anti-TNF-Treated Patients With Inflammatory Bowel Disease.

BACKGROUND: Extra-intestinal manifestations (EIMs) can impact morbidity in patients with inflammatory bowel diseases (IBD; Crohn's disease [CD] and ulcerative colitis [UC]). This study compared incidence rates of EIMs in patients with moderate to severe IBD receiving gut-selective vedolizumab (VDZ) vs those receiving systemic anti-tumor necrosis factor (anti-TNF) therapies. METHODS: Adult IBD patients receiving VDZ or anti-TNFs were identified from the MarketScan claims database from September 28, 2012, through September 30, 2016. Incidence rates of EIMs were compared between the 2 cohorts. Descriptive analyses were performed for all courses of treatment. Generalized linear models estimated the impact of treatment on the likelihood of developing EIMs. RESULTS: Compared with patients receiving anti-TNF therapy, VDZ-treated CD patients were 28% more likely to develop "any EIMs" (adjusted incident rate ratio [IRR], 1.28; 95% confidence interval [CI], 1.02-1.62). Specifically, CD patients treated with VDZ were more likely to develop erythema nodosum (IRR, 4.29; 95% CI, 1.73-10.64), aphthous stomatitis (IRR, 3.73; 95% CI, 1.51-9.23), episcleritis/scleritis (IRR, 2.51; 95% CI, 1.02-6.14), arthropathy (IRR, 1.45; 95% CI, 1.15-1.84), primary sclerosing cholangitis (PSC) (IRR, 7.79; 95% CI, 3.32-18.27), and uveitis/iritis (IRR, 2.89; 95% CI, 1.35-6.18). UC patients receiving VDZ did not have a statistically significant increase in "any EIMs" vs patients receiving anti-TNFs, but were more likely to develop specific EIMs (aphthous stomatitis: IRR, 3.67; 95% CI, 1.30-10.34; pyoderma gangrenosum: IRR, 4.42; 95% CI, 1.00-19.45; and PSC: IRR, 3.44; 95% CI, 1.23-9.68). CONCLUSIONS: IBD patients receiving VDZ may be more likely to develop EIMs vs patients receiving anti-TNF therapies. The gut-selective inflammatory control of VDZ may potentially limit its clinical effect on EIM prevention.

Adalimumab Reduces Extraintestinal Manifestations in Patients with Crohn's Disease: A Pooled Analysis of 11 Clinical Studies.

INTRODUCTION: Extraintestinal manifestations (EIMs) in patients with Crohn's disease (CD) are common and associated with additional morbidity. This study aimed to evaluate the effect of adalimumab therapy on EIM resolution and identify potential predictors of EIM resolution in adult and pediatric patients with moderate to severe CD. METHODS: EIM data were pooled from 11 induction, maintenance, and open-label extension studies of adalimumab. Resolution of EIMs was evaluated at approximately 6 months and 1 year. Median time to initial EIM resolution and first EIM recurrence (reflecting durable resolution) of any EIM and specific categories of EIMs (arthritis/arthralgia, ocular, cutaneous) were calculated. A Cox model was used to determine predictors of initial and durable EIM resolution. RESULTS: At baseline, 54% (1137/2094) of patients receiving adalimumab and 51% (297/586) receiving placebo had EIMs. EIM resolution occurred in a significantly greater proportion of adalimumab versus placebo patients at 6 months (54% vs 31%; P < .001) and 1 year (60% vs 42%; P = .008). Median time to initial resolution of any EIM, arthritis/arthralgia, and cutaneous EIMs was significantly shorter in patients receiving adalimumab versus placebo. Durable resolution of any EIM and arthritis/arthralgia was significantly longer for patients receiving adalimumab versus placebo. Clinically meaningful predictors of EIM resolution included adalimumab treatment, male sex, and moderate (versus severe) disease activity at baseline. CONCLUSION: Adalimumab is effective for achieving initial and durable resolution of any EIM and, in particular, arthritis/arthralgia in patients with moderate to severe CD. Predictors of EIM resolution included adalimumab treatment and moderate disease severity. FUNDING: AbbVie.

Effect of Adalimumab on Clinical Outcomes and Health-related Quality of Life Among Patients With Ulcerative Colitis in a Clinical Practice Setting: Results From InspirADA.

BACKGROUND AND AIMS: Randomised trials have described the benefits of adalimumab [ADA] for ulcerative colitis [UC]; however, few data are available on health-related quality of life [HRQL] and health care costs in clinical practice. METHODS: InspirADA, a multicentre, prospective study, evaluated the effect of ADA in patients with moderate to severe UC treated according to usual clinical practice. Outcomes assessed were: Simple Clinical Colitis Activity Index [SCCAI] response/remission rates; changes in HRQL; all-cause direct costs; and UC-related direct and indirect costs from baseline to Week 26. RESULTS: Data from 463 patients were analysed. At Week 26, 67% (95% confidence interval [CI]: 62%, 71%) of patients achieved response; 48% [95% CI: 44%, 53%] were in remission. For the overall population, significant [all p < 0.001] improvements from baseline to Week 26 were observed for the Short Inflammatory Bowel Disease Questionnaire [SIBDQ] (mean change ± standard deviation [SD]: 17.4 ± 14.5) and the European Quality of Life-5 Dimensions-5 Level [EQ-5D-5L] (index: 0.1 ± 0.2; visual analogue scale [VAS]: 19.5 ± 25.8). Parallel improvements were seen in work productivity [11% absolute decrease in absenteeism; 25% absolute decrease in impairment while working; and 27% absolute decrease in impairment of ability to perform daily activities, all p < 0.001]. Among study completers, cumulative all-cause medical costs and UC-related medical costs were significantly [both p < 0.001] reduced by 59% and 77%, respectively, 6 months after initiation of therapy compared with the preceding 6 months. The safety profile of ADA was consistent with that observed in previous clinical trials. CONCLUSIONS: ADA therapy in usual clinical practice is effective at improving and maintaining symptomatic control, improving HRQL, and decreasing costs of medical care among patients with UC.

Interpreting Registrational Clinical Trials of Biological Therapies in Adults with Inflammatory Bowel Diseases.

BACKGROUND: The use of biologics to treat inflammatory bowel disease is supported by robust randomized controlled trials in both ulcerative colitis and Crohn's disease. Nonetheless, an understanding of the principles of clinical trial design is necessary to extrapolate study findings to clinical practice. METHODS: We conducted a review of inflammatory bowel disease registrational clinical trials of biologics to determine how differences in trial design potentially influence results and interpretation. RESULTS: Registrational trials of biological agents have used diverse patient populations, outcome measures, and designs, which makes comparisons of results among studies difficult. Key differences among trials include patient populations, choice of symptom-based measures or objective outcomes as endpoints, and overall trial design. Additional factors, including analytical methods, can also influence the interpretation of outcomes. CONCLUSIONS: The most robust evidence is derived from comparative effectiveness trials. In the absence of these, clinicians should be aware of the various methodological issues which could impact interpretation of efficacy and safety outcomes, including differences in patient population, study design, and analytic methodology.

Testing strategy to identify cases of acute hepatitis C virus (HCV) infection and to project HCV incidence rates.

Surveillance for hepatitis C virus (HCV) is limited by the challenge of differentiating between acute and chronic infections. In this study, we evaluate a cross-sectional testing strategy that identifies individuals with acute HCV infection and we estimate HCV incidence. Anti-HCV-negative persons from four populations with various risks, i.e., blood donors, Veterans Administration (VA) patients, young injection drug users (IDU), and older IDU, were screened for HCV RNA by minipool or individual sample nucleic acid testing (NAT). The number of detected viremic seronegative infections was combined with the duration of the preseroconversion NAT-positive window period (derived from analysis of frequent serial samples from plasma donors followed from NAT detection to seroconversion) to estimate annual HCV incidence rates. Projected incidence rates were compared to observed incidence rates. Projected HCV incidence rates per 100 person-years were 0.0042 (95% confidence interval [95% CI], 0.0025 to 0.007) for blood donors, 0.86 (95% CI, 0.02 to 0.71) for VA patients, 39.8 (95% CI, 25.9 to 53.7) for young IDU, and 53.7 (95% CI, 23.4 to 108.8) for older IDU. Projected rates were most similar to observed incidence rates for young IDU (33.4; 95% CI, 28.0 to 39.9). This study demonstrates the value of applying a cross-sectional screening strategy to detect acute HCV infections and to estimate HCV incidence.

Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection.

Perturbations of plasma IL-10, IL-12, IL-13, TNF-alpha, and IFN-gamma were measured longitudinally in HIV-1 seroconverting plasma donors and were compared to subjects with symptomatic primary HIV-1 infection. Control groups included uninfected patients with symptoms and risks for primary HIV-1, healthy controls, and asymptomatic plasma donors with primary HCV. IL-10, TNF-alpha, and IFN-gamma rapidly rose in acute HIV-1 infection, while IL-13 predominated in acute HCV. Subjects with symptomatic primary HIV-1 had higher cytokine levels than asymptomatic subjects, statistically significant for TNF-alpha. Cytokine alterations occurred within 7 days of detectable HIV-1 viremia, emphasizing the need to study the earliest events of infection.

Seroreversion in subjects receiving antiretroviral therapy during acute/early HIV infection.

BACKGROUND: We assessed human immunodeficiency virus (HIV) antibody seroreversion among individuals initiating antiretroviral therapy (ART) during acute/early HIV infection and determined whether seroreversion was associated with loss of cytotoxic T lymphocyte responses. METHODS: Subjects in a cohort with acute/early HIV infection (<12 months into infection) who initiated ART within 28 days after study entry and maintained HIV type 1 ribonucleic acid levels of < or =500 copies/mL for >24 weeks were selected. Two clinically available second-generation enzyme immunoassays (EIAs) and a confirmatory Western blot were used to screen subjects for antibody reversion. Those with negative screening test results underwent additional antibody testing, including a third-generation EIA, and were assessed for cytotoxic T lymphocyte responses. RESULTS: Of 87 subjects identified, 12 (14%) had negative antibody test results at the start of ART; all 12 had seroconversion, although 1 had seroconversion only on a third-generation EIA. Of the 87 subjects, 6 (7%) had seroreversion on at least 1 EIA antibody assay while receiving ART during a median follow-up of 90 weeks. The only clinical predictor of seroreversion was a low baseline "detuned" (less sensitive) antibody. Cytotoxic T lymphocyte responses to HIV Gag peptides were detected in 4 of 5 subjects with seroreversion who could be tested. All 5 who had seroreversion who stopped ART experienced virologic rebound and antibody evolution. CONCLUSIONS: HIV antibody seroconversion on second-generation EIA antibody tests may fail to occur when ART is initiated early. Seroreversion was not uncommon among subjects treated early, although cytotoxic T lymphocyte responses to HIV antigens remained detectable in most subjects. Antibody seroreversion did not indicate viral eradication. A third-generation EIA was the most sensitive test for HIV antibodies.

Prevalence of HIV-1 in blood donations following implementation of a structured blood safety policy in South Africa.

CONTEXT: The South African National Blood Service collects more than 700,000 units of blood annually from a population in which 11.4% is infected with human immunodeficiency virus 1 (HIV-1). The prevalence of HIV-1 in blood donations increased to 0.26% (1:385) in 1998, indicating that a significant number of window-period infective units were entering the blood supply (risk 3.4/100,000). OBJECTIVES: To determine whether the implementation of a new donor selection policy and educational program introduced in 1999 was associated with reductions in the incidence and prevalence of HIV-1 in blood donations and the reduced transmission risk. DESIGN: We compared the prevalence of HIV-1 in 880,534 blood donations collected from 1999 through 2000 with the 791,639 blood donations collected from 2001 through 2002. We estimated the incidence of HIV-1 in 93,378 (1999-2000) and 67,231 (2001-2002) first-time donations and the residual risk for all donations in 2001-2002 using the less-sensitive enzyme-linked immunoassay and incidence-window period model. SETTING: All blood donors in the Inland region of the South African National Blood Service were analyzed. INTERVENTION: Donor clinics in high HIV prevalence areas were closed. Programs targeting repeat donors and youth were initiated and HIV risk behavior education programs were developed. Structured donor interviews and an enhanced donor self-exclusion questionnaire were institutionalized. RESULTS: The prevalence of HIV-1 in blood donations declined from 0.17% in 1999-2000 to 0.08% in 2001-2002 after the implementation of the new donor selection and education policy. The number of high-risk donations collected decreased from 2.6% to 1.7% (P<.001), and the likelihood of these donations being infected decreased from 4.8% to 3.25%. The likelihood of first-time donors being recently infected with HIV-1 decreased from 18% to 14% (P = .07) and respective incidence of high-risk donations collected decreased from 2.6% to 1.7%. Donations from the majority black population declined from 6.6% to 4.2% (P<.001). Analysis of HIV-1 incidence in 2001-2002 suggests a residual risk of collecting a window period infectious unit of 2.6/100,000. CONCLUSION: The implementation of enhanced education and selection policies in South Africa was associated with decreased prevalence of HIV-1 in blood donations.

Prevalence, incidence, and residual risk of human immunodeficiency virus among community and replacement first-time blood donors in São Paulo, Brazil.

BACKGROUND: Concerted efforts have been directed toward recruitment of community rather than replacement donors in Brazil. Time trends and demographic correlates of human immunodeficiency (HIV) prevalence and incidence among first-time (FT) donors in Brazil were examined by donation type. HIV residual risk from FT-donor transfusions, and projected yield of p24 antigen and nucleic acid test (NAT) screening were estimated. STUDY DESIGN AND METHODS: HIV prevalence data and seroreactive specimens were obtained at Fundação Pró-Sangue/Hemocentro-de-São Paulo from 1995 to 2001. To estimate incidence, confirmed-positive samples from July 1998 through December 2001 were tested with a less-sensitive (detuned) enzyme immunoassay to detect recent seroconversions. Incidence data were used to estimate residual risk and p24 and NAT yield based on published window periods (WPs). RESULTS: HIV prevalence was 22 percent higher among the FT community donors than replacement donors (19.6 vs. 16.1 per 10,000; p < 0.01) and 48 percent higher among men than women (19.1 vs. 12.9; p < 0.01). In the multivariable logistic regression, both variables remained significant predictors of HIV prevalence. HIV prevalence decreased from 20.4 (1995) to 13.1 per 10,000 FT donations (2001). HIV incidence was 2.7 per 10,000 person-years. The estimated rate of infected antibody-negative donations was 14.9 per 1,000,000 units (95% confidence interval, 9.8-20.0). It was estimated that addition of p24 antigen, minipool NAT, and individual-donation NAT assays would detect 3.9 (2.0-5.8), 8.3 (5.3-11.3), and 10.8 (7.1-14.5) WP units per 1,000,000 FT donations, respectively. CONCLUSION: HIV incidence and residual transfusion risk estimates are approximately 10 times higher in Brazil FT donors compared to US and European FT donors. Community FT donors had higher HIV prevalence than replacement FT donors. The yield of p24 antigen or RNA screening will be low in Brazilian donors, but substantially higher than in US donors.

A new strategy for estimating risks of transfusion-transmitted viral infections based on rates of detection of recently infected donors.

BACKGROUND: Estimates for human immunodeficiency virus (HIV)-1 and hepatitis C virus (HCV) transfusion-transmitted risks have relied on incidence derived from repeat donor histories and imprecise estimates for infectious, preseroconversion window periods (WPs). STUDY DESIGN AND METHODS: By use of novel approaches, WPs were estimated by back-extrapolation of acute viral replication dynamics. Incidence was derived from the yield of viremic, antibody-negative donations detected by routine minipool nucleic acid testing (MP-NAT) of 37 million US donations (1999-2002) or from sensitive/less-sensitive HIV-1 enzyme immunoassay (S/LS-EIA) results for seropositive samples from 6.5 million donations (1999). Incidences and WPs were combined to calculate risks and project yield of individual donation (ID)-NAT. RESULTS: The HIV-1 WP from presumed infectivity (1 copy/20 mL) to ID-NAT detection was estimated at 5.6 days, and the periods from ID to MP-NAT detection and from MP-NAT to p24 detection at 3.4 and 6.0 days, respectively; corresponding estimates for HCV were 4.9, 2.5, and 50.9 days (the latter represents period from MP-NAT to HCV antibody detection). The HIV-1 incidence projected from MP-NAT yield or from S/LS-EIA data was 1.8 per 100,000 person-years, resulting in a corresponding HIV-1 transfusion-transmitted risk of 1 in 2.3 million. The HCV incidence from MP-NAT yield was 2.70 per 100,000 person-years with a corresponding risk of 1 in 1.8 million donations. Conversion from MP-NAT to ID-NAT was projected to detect two to three additional HIV-1 and HCV infectious units annually. CONCLUSIONS: MP-NAT yield and S/LS-EIA rates can accurately project transfusion risks. HCV and HIV-1 risks, currently estimated at 1 per 2 million units, could be reduced to 1 in 3 to 4 million units by ID-NAT screening.

Influence of maternal human immunodeficiency virus (HIV) co-infection on vertical transmission of hepatitis C virus (HCV): a meta-analysis.

BACKGROUND: Maternal co-infection with human immunodeficiency virus (HIV) has been implicated as a potentially important co-factor for enhanced vertical transmission of hepatitis C virus (HCV). In previous reports, however, methodological issues (notably small sample sizes) have limited accurate evaluation of the contribution of maternal co-infection with HIV on the risk of vertical transmission of HCV. METHODS: A systematic review and subsequent meta-analysis of current published and unpublished reports was performed. Odds ratios (OR) and 95% CI for individual studies were calculated with maternal HIV serostatus as the exposure measure and HCV vertical transmission as the outcome measure. Overall summary estimates were then calculated using a random effects model that estimates a weighted average of OR from individual studies. RESULTS: In total, 2382 infants from 10 studies were included in an analysis of HCV-infected mothers (defined by anti-HCV+ antibody assays) with and without concomitant HIV infection. The risk estimate (OR) of HCV vertical transmission was 2.82 (95% CI: 1.78-4.45; P = 0.00001) from anti-HCV+/HIV+ co-infected mothers compared with anti-HCV+/HIV- mothers. In a subanalysis of 1327 infants born to viraemic (HCV RNA+) mothers, the risk estimate of HCV vertical transmission was 1.97 (95% CI: 1.04-3.74; P = 0.04) from HCV viraemic/HIV+ co-infected mothers compared with HCV viraemic/HIV- mothers. CONCLUSIONS: Results from this meta-analysis of observational studies suggest that the risk of HCV vertical transmission is higher in infants born to HIV co-infected mothers.