Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540

A coarsened multinomial regression model for perinatal mother to child transmission of HIV

Background: In trials designed to estimate rates of perinatal mother to child transmission of HIV, HIV assays are scheduled at multiple points in time. Still, infection status for some infants at some time points may be unknown, particularly when interim analyses are conducted. Methods: Logistic regression models are commonly used to estimate covariate-adjusted transmission rates, but their methods for handling missing data may be inadequate. Here we propose using coarsened multinomial regression models to estimate cumulative and conditional rates of HIV transmission. Through simulation, we compare the proposed models to standard logistic models in terms of bias, mean squared error, coverage probability, and power. We consider a range of treatment effect and visit process scenarios, while including imperfect sensitivity of the assay and contamination of the endpoint due to early breastfeeding transmission. We illustrate the approach through analysis of data from a clinical trial designed to prevent perinatal transmission. Results: The proposed cumulative and conditional models performed well when compared to their logistic counterparts. Performance of the proposed cumulative model was particularly strong under scenarios where treatment was assumed to increase the risk of in utero transmission but decrease the risk of intrapartum and overall perinatal transmission and under scenarios designed to represent interim analyses. Power to estimate intrapartum and perinatal transmission was consistently higher for the proposed models. Conclusion: Coarsened multinomial regression models are preferred to standard logistic models for estimation of perinatal mother to child transmission of HIV, particularly when assays are missing or occur off-schedule for some infants.U.S. National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and Dept. of Health and Human Services (DHHS)

Access to infertility services in Canada for HIV-positive individuals and couples: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Family and pregnancy planning issues are important among human immunodeficiency virus (HIV)-positive individuals and couples. However, access to fertility services may be limited for this population. The objective of this study was to estimate the types of services available in fertility clinics in Canada for these individuals.</p> <p>Methods</p> <p>A survey was sent to all registered fertility clinics in Canada to assess the availability of services (investigations and treatment) for infertility and/or viral transmission risk reduction in achieving pregnancy. The proportion and location of clinics willing to carry out investigations and treatments were determined. Logistic regression analysis was performed to assess differences in response rates, investigations, and treatments by province and by couple scenario.</p> <p>Results</p> <p>Completed surveys were received from 23/28 (82%) of clinics across eight Canadian provinces. Seventy-eight per cent (18/23) were willing to accept HIV-positive individuals in consultation, and 52% had actually seen at least one HIV-positive man or woman in the previous year. Clinics in every province were willing to offer infertility investigations, but only clinics located in five provinces were willing to offer fertility treatments. The most commonly available treatment was intrauterine insemination for couples in which the female partner was HIV-positive (52%). Other techniques, such as sperm washing (26%) or in vitro fertilization (17%), were less commonly offered. A smaller number of clinics were willing to offer risk reduction techniques in achieving pregnancy.</p> <p>Conclusions</p> <p>Access to infertility investigations and treatments in Canada is limited and regionally dependent.</p> <p>Trial Registration</p> <p>Registered with ClinicalTrials.gov at <url>http://www.clinicaltrials.gov</url>, registration number NCT00782132.</p

HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis

Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs

What Will It Take to Eliminate Pediatric HIV? Reaching WHO Target Rates of Mother-to-Child HIV Transmission in Zimbabwe: A Model-Based Analysis

Using a simulation model, Andrea Ciaranello and colleagues find that the latest WHO PMTCT (prevention of mother to child transmission of HIV) guidelines plus better access to PMTCT programs, better retention of women in care, and better adherence to drugs are needed to eliminate pediatric HIV in Zimbabwe

Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA

<p>Abstract</p> <p>Background</p> <p>Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT.</p> <p>Methods</p> <p>In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression.</p> <p>Results</p> <p>In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections.</p> <p>More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery.</p> <p>Conclusion</p> <p>These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain.</p> <p>Trial registration</p> <p>NCT00000869</p

Are reports of mental fog from patients with idiopathic hypersomnia mediated by objective measures of daytime sleepiness?

Introduction: Objective evidence of pathological sleepiness (i.e. MSLT \u3c 8) is required for an Idiopathic Hypersomnia (IH) diagnosis. Aside from EDS, IH patients report mental fatigue and inability to concentrate. The relation between these two symptoms is not well understood. Methods: To address this issue we produced a correlation matrix using blinded data from all 21 subjects who, to date, completed the IH202 trial (ARISE2). This is a Phase II, double blind, randomized 2-period crossover study in evaluating the safety and efficacy of an oral GABA antagnoist (BTD-001). Patients are randomized to either two weeks of active treatment followed by 2-week washout and then two weeks of placebo or placebo followed by washout and then active treatment. Included in the analysis were Idiopathic Hypersomnia Symptom Diary (IHSD) 4 items, the PGIC, SF-36, reports of sleepiness (ESS) and objective measures of sleepiness (MWT and PVT). We produced 2 correlational matrices (Pearson Correlation Coefficients) using data from the 21 subjects who completed both treatment periods in the ARISE2 study. We produced this matrix using blinded pooled data from treatment period 1 as well as treatment period 2. Importantly, approximately half the subjects in treatment period 1 were on drug and the other half were on placebo. In treatment period 2, those previously on placebo were on active treatment and those previously getting active were on placebo. The advantage of this approach is the ability to identify correlates of patient\u27s evaluation of improvement in a double-blind manner. As there were multiple correlations performed, we treated treatment periods 1 and 2 correlations as replicates and are considering only those that were significant in both matrices. Results: There were 55 correlations calculated in each treatment period. Across 55 correlations, 24 were not significant in either treatment periods, 19 were significant at one of the treatment periods, and 12 were significant in both treatment periods. Patient evaluation of improvement (i.e. PGIC) correlated on both occasions with only Mental Fog and Exhausted scales Scale of the IHSD and the vitality sub-scale of the SF-36. Neither measure of the 2 objective assays of sleepiness (MWT and PVT) correlated even once with subject\u27s estimate of improvement. Interestingly, neither of the 2 objective assays of sleepiness correlated even once with the patient report of sleepiness (i.e. ESS). This suggests, as authors have stated previously that the reports of sleepiness in IH relate more to mental fatigue rather than physiological sleepiness per se. In contrast the mental fog scale, correlated with all 3 of the other IHSD subscales, the subjective sleepiness (ESS) as well as patients´ judgments about efficacy (PGIC). Discussions: These data support the positions that: a) mental fog is independent of objective assays of sleepiness and b) objective assays of sleepiness may not be appropriate efficacy endpoints in IH clinical trials

Characteristics of subjects excluded form an idiopathic hypersomnia randomized clinical trial (ARISE2)

Introduction: Research of the safety and efficacy of new treatments is conducted via randomized controlled trials (RCTs). Rigorous inclusion and exclusion criteria are standard practice in high-quality RCTs. Inclusion criteria define the target population investigated while exclusion criteria identify participants with characteristics that could increase risk for a negative outcome. To establish a diagnosis of Idiopathic Hypersomni (IH), patients must have daytime sleepiness, impairment in daytime function, normal or extended sleep and exclusion of other hypersomnolence causes. The present report sought to identify the frequency and primary reasons subjects were excluded from ARISE2, a Phase 2 RCT in IH. Methods: Potential study participants with a preliminary diagnosis of IH were screened by a committee of 3 independent sleep diseases experts (authors, AA. LR, TR). The final decision regarding eligibility was determined by a consensus of the committee working with the following pre-specified guidelines: 1. Sleep history consistent with a diagnosis of IH and inconsistent with other causes of hypersomnolence (e.g. SRBD, narcolepsy, insufficient sleep), 2. Historical PSG adequately documenting, TST, SE, sleep stage distribution and an AHI and PLMAI \u3c 15, 3. Historical MSLT showing a mean sleep latency \u3c 8.0m and \u3c 2 REM onsets, 4. Historical and current medication use focusing on potential REM suppressing medications, 5. Current sleep diary demonstrating average \u3e 7 hours in bed nightly over the past week, 6. Current ESS \u3e10, 7. Current Mental fog score from Idiopathic Hypersomnia Symptom Diary (0 to 10 scale) of \u3e6 over the preceding week. Results: Thus far, 134 subjects were reviewed by the committee. Of these, 94(68%) were excluded. The major reasons were : historic MSLT\u3e8 (22), discontinued interest (20), failed to show mental fog score\u3e 5 (12), failed to demonstrate \u3e7 hours mean nocturnal sleep time (10), unable to comply with study restrictions (prohibited concomitant medication washout, alcohol, nicotine, caffeine) (12), ESS\u3c 10 (6), other diagnosed causes of hypersomnolence (5), circadian rhythm sleep disorders (2), abnormal clinical labs (2), BMI\u3e35 (1), CPAP use (1), and elevated suicidality score (1). Conclusion: A majority of patients with a preliminary diagnosis of IH failed study screening due to inability to meet inclusion criteria necessary for the IH diagnosis. Other major reasons include patients withdrawing consent due to inability or unwillingness to commit for the duration of the study as well as inability to comply with protocol (i.e., use of alcohol, nicotine, caffeine or concomitant medications). It is possible that the subjects enrolled are not fully representative of the general IH population or IH may be overly diagnosed in the community setting. Polysomnographic and MSLT data may help enhance the specificity of IH diagnosis when it is coupled with the clinical history. Alternative methods such as all-comer studies and open label clinical case series may be needed to contextualize the results of the more rigorous clinical studies