Prevention Clinical Trials Research Articles

‘Hold on’ (Bambelela)! Lyrical interpretations of participation in an HIV prevention clinical trial

During a five-day workshop, former clinical trial participants and local musicians wrote the lyrics and recorded a song about an HIV prevention trial. Born of concerns about misconceptions regarding experimental drug trials, the aim was to engender engagement with medical researchers and open dialogue about the risks and benefits of trial participation. Composing lyrics that highlighted their credibility as communicators of medical scientific knowledge and their selfless sacrifice to stem the transmission of HIV, women performed their social positioning and cultural authority in contrast to men as well as other women not part of the trial. While involvement in HIV prevention initiatives often attracts stigma, scorn and criticism, the song’s lyrics highlighted women’s new-found identities as heroines searching for a solution to the spread of HIV, challenging these stereotypes. Methodologically, the paper describes a novel approach that uses artistic expression for public engagement with biomedical research.

Prevention and Treatment of Pediatric HIV Infection

The goal of this paper is to review the prevention of mother-to-child HIV transmission (PMTCT) research that informed World Health Organization (WHO) guidelines for PMTCT and describe the impact of worldwide scale-up of PMTCT programs and antiretroviral therapy (ART) coverage. The impact of these interventions on new pediatric infections and infected children’s morbidity and mortality in sub-Saharan Africa are reviewed. The IMPAACT PROMISE study demonstrated that triple therapy consisting of tenofovir (TDF), lamivudine (3TC), and lopinavir/ritonavir (LPVr) or zidovudine (AZT), 3TC, and LPVr initiated in the first trimester reduced vertical transmission at 2 weeks of age to 0.6% and 0.5%, respectively, supporting the current WHO Option B+ recommendation for PMTCT. However, increased adverse pregnancy outcomes in the AZT- and TDF-based triple therapy arms were reported when compared with the AZT prophylaxis arm (low birth weight [20.4% and 16.9% vs. 8.9%; p = 0.004] and premature deliveries [19.7% and 18.5% vs. 13.5%; p = 0.09], respectively). Implementation of Option B+ for PMTCT has led to significant reductions in vertical transmission rates, including elimination of new pediatric infections in some countries. The WHO declared elimination of mother-to-child HIV transmission (MTCT) in Cuba in 2015 and in Armenia, Belarus, and Thailand in 2016. Globally, new pediatric HIV infections have declined significantly since the introduction of effective antiretroviral regimens for PMTCT. Perinatal HIV prevention clinical trials conducted in sub-Saharan Africa informed WHO PMTCT guidelines which led to implementation of PMTCT programs worldwide, leading to a 47% reduction in new pediatric infections since 2009. Support from The United States President's Emergency Plan for AIDS Relief (PEPFAR), the Global Fund for AIDS, Tuberculosis and Malaria, and UN agencies has enabled scale-up of national PMTCT programs, and increased antiretroviral coverage (47% globally) for infected children has led to a decline in HIV/AIDS-related mortality in children. Implementation strategies that improve retention in care and adherence to ART in pregnant and breastfeeding HIV-infected women is critical to ensure that more countries achieve the elimination of MTCT (eMTCT) targets. Assessing the effectiveness of new antiretroviral drugs, including fixed-dose combinations and long-acting formulations, is key to improving ART adherence and reducing the emergence of viral resistance mutations. In addition, interventions to prevent HIV transmission in adolescents and young adults is critical for reducing new HIV infections worldwide. Innovative interventions to improve adherence to ART are required to further improve the survival of HIV-infected children and adolescents.

Substance use patterns of HVTN phase I clinical trial participants: Enrollment, risk reduction counseling and retention

BackgroundThe primary objectives of HIV Vaccine Trials Network (HVTN) phase 1 preventive HIV vaccine clinical trials are to assess safety and immune response to study products. Participant alcohol and drug use may affect adherence, retention, and risk of HIV infection. Data on the effects of substance use are limited to medical care compliance and treatment adherence in HIV infected participants. To our knowledge, there are no data assessing substance use and retention in these vaccine trials. MethodsWe performed a meta-analysis on substance use and its impact on retention in HVTN phase I trials that recruited participants demonstrating lower risk profiles for HIV infection. Our analysis included data from 10 HVTN phase 1 clinical trials conducted between February 2009 and September 2014 in the Americas and Switzerland that utilized the identical interviewer-administered behavioral risk assessment questionnaire to capture participant self-report of substance use in the previous six months. Chi Square tests were used to assess statistical differences between variables. ResultsAmong the 964 participants, 170 (18%) missed a clinic visit and 78 (8%) terminated early from clinic follow-up; 75/774 (10%) on studies with multiple vaccination timepoints did not complete their vaccinations. Neither frequency of alcohol use, binge drinking, marijuana, nor other drug use reported at screening visits were associated with the three adherence/retention measures. Binge drinking was associated with higher rates of unprotected sex while drunk (p < .001). ConclusionsLight to moderate alcohol use does not negatively impact adherence or retention in phase I clinical trials. Based on these screening data and the low infection rate of participants during the trial period, the screening process for participation in HVTN phase 1 trials has largely been successful in enrolling and retaining individuals with lower risk profiles. Focusing on binge drinking and increased HIV/STI risk during risk reduction counseling may be warranted.

Partnerships Between a University-Affiliated Clinic and Community-Based Organizations to Reach Black Men Who Have Sex With Men for PrEP Care.

Partnerships Between a University-Affiliated Clinic and Community-Based Organizations to Reach Black Men Who Have Sex With Men for PrEP Care.

Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development.

Selenium (Se)-containing molecules exert antioxidant properties and modulate targets associated with tumor growth, metastasis, angiogenesis, and drug resistance. Prevention clinical trials with low-dose supplementation of different types of Se molecules have yielded conflicting results. Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent. Further, Se pretreament offered selective protection of normal tissues from drug-induced toxicity, thereby allowing higher dosing than maximum tolerated doses.These enhanced therapeutic effects were associated with inhibition of hypoxia-inducible factor 1- and 2-alpha (HIF1α, HIF2α) protein, nuclear factor (erythyroid-derived 2)-like 2 (Nrf2) and pair-related homeobox-1 (Prx1) transcription factors, downregulation of oncogenic- and upregulation of tumor suppressor miRNAs. This review provides: 1) a brief update of clinical prevention trials with Se; 2) advances in the use of specific types, doses, and schedules of Se that selectively modulate antitumor activity and toxicity of anti-cancer drugs; 3) identification of targets selectively modulated by Se; 4) plasma and tumor tissue Se levels achieved after oral administration of Se in xenograft models and cancer patients; 5) development of a phase 1 clinical trial with escalating doses of orally administered selenomethionine in sequential combination with axitinib to patients with advanced clear cell renal cell carcinoma; and 6) clinical prospects for future therapeutic use of Se in combination with anticancer drugs.

Qualitative features in clinical trials: coordinates for prevention of passive and active misconduct

&lt;p class="abstract"&gt;&lt;span lang="EN-IN"&gt;For many years, the quality concept in clinical trials has been discussed and recommended by Good Clinical Practice (GCP) guidelines. Regulatory Authorities and also the Public Involvement anticipate that the pharmaceutical industry will concentrate on creating quality frameworks amid the arranging and leading of conventions of controlled protocols. Nevertheless, many factors have been suggested as contributing to the occurrence of scientific misconduct within the research field, such as: personal and financial interests, site monitoring, available resources, workload, competition among investigators, and the implicit &lt;/span&gt;&lt;span lang="EN"&gt;consent of sponsors. The negligence on data fraud represents not only omission but misconduct as well, in this case, a passive attitude intrinsically related to the act of transgression. A properly culture of research must be based on a fundamental ethos of integrity, openness and honest work of high quality in all parts of the research process. &lt;/span&gt;&lt;span lang="EN-IN"&gt;There is a need to change the focus from inspection-based quality improvement to planned systematic quality management within clinical trials. In search for a monitoring improvement, a full statistical way to deal with information recognition comprises of executing however many measurable tests as could be allowed on whatever number clinical information factors as could be expected under varied circumstances. Adoption of specific and preventive clinical trial monitoring procedures can identify potential misconduct and data fraud leading to improvement in overall data quality and scientific reports&lt;/span&gt;&lt;span lang="EN-AU"&gt;. &lt;/span&gt;&lt;/p&gt;

Assessment of Instrumental Activities of Daily Living in Older Adults with Subjective Cognitive Decline Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

Continuing advances in the understanding of Alzheimer's disease progression have inspired development of disease-modifying therapeutics intended for use in preclinical populations. However, identification of clinically meaningful cognitive and functional outcomes for individuals who are, by definition, asymptomatic remains a significant challenge. Clinical trials for prevention and early intervention require measures with increased sensitivity to subtle deficits in instrumental activities of daily living (IADL) that comprise the first functional declines in prodromal disease. Validation of potential endpoints is required to ensure measure sensitivity and reliability in the populations of interest. The present research validates use of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for performance-based assessment of IADL functioning in older adults (age 55+) with subjective cognitive decline. Cross-sectional validation study. All participants were evaluated on-site at NeuroCog Trials, Durham, NC, USA. Participants included 245 healthy younger adults ages 20-54 (131 female), 247 healthy older adults ages 55-91 (151 female) and 61 older adults with subjective cognitive decline (SCD) ages 56-97 (45 female). Virtual Reality Functional Capacity Assessment Tool; Brief Assessment of Cognition App; Alzheimer's Disease Cooperative Study Prevention Instrument Project - Mail-In Cognitive Function Screening Instrument; Alzheimer's Disease Cooperative Study Instrumental Activities of Daily Living - Prevention Instrument, University of California, San Diego Performance-Based Skills Assessment - Validation of Intermediate Measures; Montreal Cognitive Assessment; Trail Making Test- Part B. Participants with SCD performed significantly worse than age-matched normative controls on all VRFCAT endpoints, including total completion time, errors and forced progressions (p≤0001 for all, after Bonferonni correction). Consistent with prior findings, both groups performed significantly worse than healthy younger adults (age 20-54). Participants with SCD also performed significantly worse than controls on objective cognitive measures. VRFCAT performance was strongly correlated with cognitive performance. In the SCD group, VRFCAT performance was strongly correlated with cognitive performance across nearly all tests with significant correlation coefficients ranging from 0.3 to 0.7; VRFCAT summary measures all had correlations greater than r=0.5 with MoCA performance and BAC App Verbal Memory (p<0.01 for all). Findings suggest the VRFCAT provides a sensitive tool for evaluation of IADL functioning in individuals with subjective cognitive decline. Strong correlations with cognition across groups suggest the VRFCAT may be uniquely suited for clinical trials in preclinical AD, as well as longitudinal investigations of the relationship between cognition and function.

Vaccine Development Strategies, Progresses and Challenges for Human Immunodeficiency Virus (HIV): A Review

Human immunodeficiency virus is classified under the Retroviridae family and identified as a causative agent of acquired immunodeficiency syndrome (AIDS).Since Human immunodeficiency virus (HIV) is identified as causative agent of AIDS, about 39 million people have been died and 78 million people have been infected worldwide. Despite tremendous efforts are being made to develop successful diagnosis, treatment and prevention methods, and to develop HIV vaccine the effort remains great challenge for researchers, due to extreme genetic variability of the virus. Even though vaccination of HIV is the most promising, cost effective and feasible intervention strategy to control and eradicate HIV disease route and transmission, still now we are struggling to find an elusive vaccine after thirty years and disappointing results are recorded from previous clinical trials, except the promising RV144 HIV vaccine which is phase III clinical trial with the modest vaccine efficacy. The contribution of this study is to reveal the challenges to found potent HIV vaccine during the last decades, significant lessons learnt about the basic virology, pathogenesis, immunology, HIV/AIDS treatment and HIV infection prevention and significant findings and clinical trials progresses which are currently open the way to some extent to hope that HIV vaccine development is possible.

Situated Prevention: Framing the “New Dementia”

This article is about the recent and profound changes in the conceptualization of dementia, especially the turn towards prevention. The main argument is that more attention needs to be paid to "situated prevention" - the framing of internationally circulating data on the "new dementia" in different contexts. After introducing some of the more problematic issues related to the "new dementia," a first comparison of major preventive clinical trials in Europe and in North America will be provided. The major insight stemming from situating the global message of preventing dementia is recognition of the responsibility researchers and policy makers bear with respect to the implicit and potential moral narratives in emerging scientific landscapes.

Bayesian Modeling and Inference for Nonignorably Missing Longitudinal Binary Response Data with Applications to HIV Prevention Trials.

Missing data are frequently encountered in longitudinal clinical trials. To better monitor and understand the progress over time, one must handle the missing data appropriately and examine whether the missing data mechanism is ignorable or nonignorable. In this article, we develop a new probit model for longitudinal binary response data. It resolves a challenging issue for estimating the variance of the random effects, and substantially improves the convergence and mixing of the Gibbs sampling algorithm. We show that when improper uniform priors are specified for the regression coefficients of the joint multinomial model via a sequence of one-dimensional conditional distributions for the missing data indicators under nonignorable missingness, the joint posterior distribution is improper. A variation of Jeffreys prior is thus established as a remedy for the improper posterior distribution. In addition, an efficient Gibbs sampling algorithm is developed using a collapsing technique. Two model assessment criteria, the deviance information criterion (DIC) and the logarithm of the pseudomarginal likelihood (LPML), are used to guide the choices of prior specifications and to compare the models under different missing data mechanisms. We report on extensive simulations conducted to investigate the empirical performance of the proposed methods. The proposed methodology is further illustrated using data from an HIV prevention clinical trial.

Alzheimer's disease in Down syndrome: An overlooked population for prevention trials

The discovery that adults with Down syndrome (DS) have neuropathological features identical to individuals with sporadic Alzheimer's disease (AD) played a key role in the identification of the amyloid precursor protein gene on chromosome 21 and resulted in the amyloid cascade hypothesis. Individuals with DS have a lifetime risk for dementia in excess of 90%, and DS is now acknowledged to be a genetic form of AD similar to rare autosomal-dominant causes. Just as DS put the spotlight on amyloid precursor protein mutations, it is also likely to inform us of the impact of manipulating the amyloid pathway on treatment outcomes in AD. Ironically, however, individuals with DS are usually excluded from AD trials. This review will discuss primary and secondary prevention trials for AD in DS and the potential barriers and solutions to such trials and describe the Europe-wide Horizon21 Consortium to establish a DS-AD prevention clinical trials network.

Malawian women’s experiences of rules regarding participation in HIV prevention and treatment clinical trials during pregnancy

Malawian women’s experiences of rules regarding participation in HIV prevention and treatment clinical trials during pregnancy

The Latent Structure and Test-Retest Stability of Connected Language Measures in the Wisconsin Registry for Alzheimer's Prevention (WRAP).

While it is well known that discourse-related language functions are impaired in the dementia phase of Alzheimer's Disease (AD), the presymptomatic temporal course of discourse dysfunction are not known earlier in the course of AD. To conduct discourse-related studies in this phase of AD, validated psychometric instruments are needed. This study investigates the latent structure, validity, and test-retest stability of discourse measures in a late-middle-aged normative group who are relatively free from sporadic AD risk factors. Using a normative sample of 399 participants (mean age = 61), exploratory factor analyses (EFA) and confirmatory factor analyses (CFA) were conducted on 18 measures of connected language derived from picture descriptions. Factor invariance across sex and family history and longitudinal test-retest stability measures were calculated. The EFA revealed a four-factor solution, consisting of semantic, syntax, fluency, and lexical constructs. The CFA model substantiated the structure, and factors were invariant across sex and parental history of AD status. Test-retest stability measures were within acceptable ranges. Results confirm a factor structure that is invariant across sex and parental AD history. The factor structure could be useful in similar cohorts designed to detect early language decline in investigations of preclinical or clinical AD or as outcome measures in clinical prevention trials.

Impact of the Dapivirine Vaginal Ring on Sexual Experiences and Intimate Partnerships of Women in an HIV Prevention Clinical Trial: Managing Ring Detection and Hot Sex.

Vaginally-inserted HIV prevention methods have been reported to impact the sexual experience for women and their partners, and hence impacts acceptability of and adherence to the method. We analyzed in-depth interviews and focus group discussions about participants' sexual experiences while wearing the ring, collected during the MTN-020/ASPIRE phase 3 safety and effectiveness trial of a dapivirine vaginal ring for HIV prevention in Malawi, South Africa, Uganda, and Zimbabwe. Most women reported that partners did not feel the ring during sex, however, women felt they had to manage their partners' interaction with or reaction to the ring. In maintaining positive relationships, women were concerned about partners' discovering ring use and about ensuring that partners had a good sexual experience with them. Finally women were concerned about how they themselves experienced sex with the ring. Some found that the ring made the vaginal environment more desirable for their partners and themselves.

Variation in levels of the flavone tricin in bran from rice genotypes varying in pericarp color

The flavone tricin has recently been shown to have numerous health benefits and has been proposed as a safe candidate for clinical trials of cancer prevention. One dietary source of tricin is rice bran. There are only a few reports of tricin levels in rice bran. Here we used LC/MS analysis of rice bran extracts to compare the tricin content, as well as some additional flavonoid components, of twenty rice bran samples from genotypes with light brown, brown, red, and purple pericarp coloring. There was a wide range in tricin levels among the samples, which ranged from 1.2 to 10.0 μg g−1 bran. Overall, the purple pericarp genotypes had higher levels of tricin, as well as a broader range of flavonoid types. This is the first report of the flavone tricin in purple pericarp genotypes, which are well known for their anthocyanin pigments.

Implementation of a Novel Adherence Monitoring Strategy in a Phase III, Blinded, Placebo-Controlled, HIV-1 Prevention Clinical Trial

Placebo-controlled HIV-1 prevention trials of pre-exposure prophylaxis (PrEP) have not generally used concurrent measurement of adherence because of the potential risk of unblinding. However, several pre-exposure prophylaxis trials for HIV-1 prevention among women failed to show effectiveness because of low product adherence. Evaluation of product adherence objectively during a study provides the opportunity for strengthening adherence activities at sites having low adherence. During MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine intravaginal ring, we implemented an adherence monitoring system. Monitoring began in quarter 1 (Q1) 2013 and continued through the conclusion of the trial. Blood plasma was collected quarterly and tested for dapivirine concentrations while maintaining blinding among study team members involved in participant management. Dapivirine concentrations >95 pg/mL, reflecting >8 hours of continuous use, were assessed as signaling product use. Study leadership monitored results on a monthly basis and provided feedback to site investigators. Experiences were shared across sites to motivate staff and counsel participants to strive toward higher adherence levels. An upward trend in adherence was observed (P < 0.0001); the proportion of samples from subjects in the active arm with dapivirine >95 pg/mL increased from 63% in Q1 2013 to 84% by Q1 2015. Ongoing drug level testing as a marker of adherence in MTN-020/ASPIRE demonstrates the feasibility of real-time adherence monitoring while maintaining study blinding at the level of participants, sites, and study leadership. This approach is novel for large-scale effectiveness studies for HIV-1 prevention.

Pressure Ulcers: Development and psychometric evaluation of the Patient Knowledge of Pressure Ulcer Prevention Instrument (KPUP)

Aim: Patient’s right’s to have a central part in the healthcare process is an important aspect of health care provision1. Benefits include enhanced motivation and knowledge about health and illness, and increased capacity to monitor and look after themselves2. Patient involvement in pressure ulcer prevention tends to be limited, as this aspect of care has been largely viewed as being in the domain of the trained health care professional3. To evaluate the outcomes of a planned patient led pressure ulcer prevention clinical trial, a validated tool to measure patient knowledge was essential. However, the researcher was unable to find a validated tool and thus the development and psychometric evaluation of KPUP4 instrument was necessary. Method: Step 1 involved development of the questionnaire, to explore knowledge, attitudes and health behaviours, related to pressure ulcer prevention. Firstly content validity was undertaken. Items with a Content Validity Index of .78, or higher were included. Step 2 involved psychometric evaluation of the KPUP4 among a cohort of 200 older persons on a test/retest basis, following ethical approval and consent. Results / Discussion: Data were analysed, stored and presented using SPSS version 23.05. Cronbach’s alpha was relatively stable (a=. 58 for test, a=. 54 for retest) for the instrument. The correlation between the test/retest computed score was positive (r=. 60). Conclusion: The development of the KPUP4 as a reliable and valid instrument to assess patient’s knowledge of, and attitudes to behaviours towards pressure ulcer prevention is an important step in order to evaluate the impact of education programmes on patients.

Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk.

Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/ insulin resistance (IR) traits and signaling pathways, using data from 704 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment–insulin resistance) on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway–related genetic variants) had different associations with CRC risk between strata, and the proportion of the SNP–cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

Statin use and risk of developing diabetes: results from the Diabetes Prevention Program

ObjectiveSeveral clinical trials of cardiovascular disease prevention with statins have reported increased risk of type 2 diabetes (T2DM) with statin therapy. However, participants in these studies were at relatively low...

Pharmacological and Non-pharmacological Treatments for Stroke Prevention in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is associated with significant risk of stroke and other thromboembolic events, which can be effectively prevented using oral anticoagulation (OAC) with either vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, or edoxaban. Until recently, VKAs were the only available means for OAC treatment. NOACs had similar efficacy and were safer than or as safe as warfarin with respect to reduced rates of hemorrhagic stroke or other intracranial bleeding in the respective pivotal randomized clinical trials (RCTs) of stroke prevention in non-valvular AF patients. Increasing “real-world” evidence on NOACs broadly confirms the results of the RCTs. However, individual patient characteristics including renal function, age, or prior bleeding should be taken into account when choosing the OAC with best risk–benefit profile. In patients ineligible for OACs, surgical or interventional stroke prevention strategies should be considered. In patients undergoing cardiac surgery for other reasons, the left atrial appendage excision, ligation, or amputation may be the best option. Importantly, residual stumps or insufficient ligation may result in even higher stroke risk than without intervention. Percutaneous left atrial appendage occlusion, although requiring minimally invasive access, failed to demonstrate reduced ischemic stroke events compared to warfarin. In this review article, we summarize current treatment options and discuss the strengths and major limitations of the therapies for stroke risk reduction in patients with AF.