Maximizing participant retention in a phase 2B HIV prevention trial in Kampala,Uganda: The MTN-003 (VOICE) Study

Background: The success of longitudinal trials depends greatly on using effective strategies to retain participants and ensure internal validity, maintain sufficient statistical power, and provide for the generalizability of study results.

Objective: This paper describes the challenges and specific strategies used to retain participants in a Phase 2B safety and effectiveness study of daily oral and vaginal tenofovir formulations for the prevention of HIV-1 infection in the MTN-003 (VOICE) trial in Kampala, Uganda.

Methods: Once enrolled, participants were seen every 28 days at the research site and their study product was re-filled. Challenges to retention included a mobile population, non-disclosure of study participation to spouse/family, and economic constraints. Strategies used to maintain high participation rates included the use of detailed locator information, a participant tracking database, regular HIV/STI testing, and the formation of close bonds between staff and subjects.

Results: We enrolled 322 women out of the 637 screened. The overall retention rate was 95% over a 3 year follow up period. Only 179 (3%) out of the 6124 expected visits were missed throughout study implementation. Reasons for missed visits included: participants thinking that they did not need frequent visits due to their HIV negative status, time constraints due to commercial sex work, and migration for better employment.

Conclusions: With the implementation of multi-faceted comprehensive follow-up and retention strategies, we achieved very high retention rates in the MTN-003 study. This paper provides a blueprint for effective participant retention strategies for other longitudinal HIV prevention studies in resource-limited settings in Sub-Saharan Africa.     

A multi-site community randomized trial of community health workers to provide counseling and support for patients newly entering HIV care in rural Ethiopia: study design and baseline implementation

Background: Although HIV therapy is delivered to millions globally, treatment default (especially soon after entering care) remains a challenge. Community health workers (CHWs) can provide many services for people with HIV, including in rural and resource-limited settings.

Objectives: We designed and implemented a 32 site community randomized trial throughout southern Ethiopia to assess an intervention using CHWs to improve retention in HIV care.

Methods: Sixteen district hospital and 16 local health center HIV clinics were randomized 1:1 to be intervention or control sites. From each site, we enrolled adults newly entering HIV care. Participants at intervention sites were assigned a CHW who provided: HIV and health education; counseling and social support; and facilitated communication with HIV clinics. All participants are followed through three years with annual health surveys, plus HIV clinic record abstraction including clinic visit dates. CHWs record operational data about their client contacts.

Results: 1799 HIV patients meeting inclusion criteria were enrolled and randomized: 59% were female, median age = 32 years, median CD4 + count = 263 cells/mm³, and 41% were WHO Stage III or IV. A major enrollment challenge was fewer new HIV patients initiating care at participating sites due to shortage of HIV test kits. At intervention sites, 71 CHWs were hired, trained and assigned to clients. In meeting with clients, CHWs needed to accommodate to various challenges, including HIV stigma, distance, and clients lacking cell phones.

Conclusions: This randomized community HIV trial using CHWs in a resource-limited setting was successfully launched, but required flexibility to adapt to unforeseen challenges.     

Follow YOUR Heart: development of an evidence-based campaign empowering older women with HIV to participate in a large-scale cardiovascular disease prevention trial

Background: Women’s under-representation in HIV and cardiovascular disease (CVD) research suggests a need for novel strategies to ensure robust representation of women in HIV-associated CVD research.

Objective: To elicit perspectives on CVD research participation among a community-sample of women with or at risk for HIV, and to apply acquired insights toward the development of an evidence-based campaign empowering older women with HIV to participate in a large-scale CVD prevention trial.

Methods: In a community-based setting, we surveyed 40 women with or at risk for HIV about factors which might facilitate or impede engagement in CVD research. We applied insights derived from these surveys into the development of the Follow YOUR Heart campaign, educating women about HIV-associated CVD and empowering them to learn more about a multi-site HIV-associated CVD prevention trial: REPRIEVE.

Results: Endorsed best methods for learning about a CVD research study included peer-to-peer communication (54%), provider communication (46%) and video-based communication (39%). Top endorsed non-monetary reasons for participating in research related to gaining information (63%) and helping others (47%). Top endorsed reasons for not participating related to lack of knowledge about studies (29%) and lack of request to participate (29%). Based on survey results, the REPRIEVE Follow YOUR Heart campaign was developed. Interwoven campaign components (print materials, video, web presence) offer provider-based information/knowledge, peer-to-peer communication, and empowerment to learn more. Campaign components reflect women’s self-identified motivations for research participation – education and altruism.

Conclusions: Investigation of factors influencing women’s participation in HIV-associated CVD research may be usefully applied to develop evidence-based strategies for enhancing women’s enrollment in disease-specific large-scale trials. If proven efficacious, such strategies may enhance conduct of large-scale research studies across disciplines.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

Y-Chromosome haplotypes reveal relationships between populations of the Arabian Peninsula,North Africa and South Asia

Background: The United Arab Emirates (UAE) is positioned at the crossroads of human migration out of Africa and through to Asia and Europe.

Aim: To compare the degree of genetic diversity of the Arabian UAE population with populations in other countries from the Middle East, South Asia and North Africa.

Subjects and methods: Twenty-seven Y-STR were analysed in 217 individuals. Y-STR haplotypes from this study were compared to population data stored in YHRD, using MDS and AMOVA.

Results: Two hundred and twelve haplotypes were observed in the 217 individuals studied. Although the reduction in Y-STR loci from 27 to 17 resulted in a decrease in discriminatory power, comparisons of populations were possible. The UAE population clustered closer with other populations of the Middle East. The South Asian and North African populations were separated by Middle Eastern populations in between both clusters.

Conclusion: This is the first study to report the diversity of a population of the Arabian Peninsula using 27 Y-STR. MDS plots show that Middle Eastern populations are positioned in the centre, with African, Asian and European populations around the Arab population cluster. The findings of this study are consistent with this region being at the epicentre of human migration between continents.     

Linking between genetic structure and geographical distance: Study of the maternal gene pool in the Ethiopian population

Background The correlation between genetics and geographical distance has already been examined through the study of the dispersion of human populations, especially in terms of uniparental genetic markers.

Aim The present work characterises, at the level of the mitochondrial DNA (mtDNA), two new samples of Amhara and Oromo populations from Ethiopia to evaluate the possible pattern of distribution for mtDNA variation and to test the hypothesis of the Isolation-by-Distance (IBD) model among African, European and Middle-Eastern populations.

Subjects and methods This study analysed 173 individuals belonging to two ethnic groups of Ethiopia, Amhara and Oromo, by assaying HVS-I and HVS-II of mtDNA D-loop and informative coding region SNPs of mtDNA.

Results The analysis suggests a relationship between genetic and geographic distances, affirming that the mtDNA pool of Africa, Europe and the Middle East might be coherent with the IBD model. Moreover, the mtDNA gene pools of the Sub-Saharan African and Mediterranean populations were very different.

Conclusion In this study the pattern of mtDNA distribution, beginning with the Ethiopian plateau, was tested in the IBD model. It could be affirmed that, on a continent scale, the mtDNA pool of Africa, Europe and the Middle East might fall under the IBD model.     

ALK protein expression in pulmonary adenocarcinoma of Tunisian patients

Background. It is now necessary to determine ALK status in order to use targeted therapy. Aim: herein, we assess immunohistochemical profile of ALK protein in a series of Tunisian patients with pulmonary adenocarcinoma.

Materials and Methods. ALK protein expression was studied applying the D5F3 antibody with a fully automated Ventana CDx technique on a series of 19 patients.

Results. Positive ALK expression was found in one case (5.2%) corresponding to a papillary adenocarcinoma which showed a strong granular and homogenous cytoplasmic staining. The patient was a 30-years-old woman.

Conclusion. The frequency of positive ALK expression based on immunohistochemistry in our series was similar to that reported in the world literature.     

False-positive HIV diagnoses: lessons from Ugandan and Russian research cohorts

Background: Research studies rely on accurate assessment of entry criteria in order to maintain study integrity and participant safety, however, challenges can exist with HIV studies in international settings.

Objective: Examine the unexpectedly high proportion of study participants with an undetectable HIV viral load found in Ugandan and Russian research cohorts meeting antiretroviral therapy (ART)-naïve entry criteria.

Methods: Russian participants with documented HIV and ART-naïve status were recruited between 2012 and 2015 from clinical and non-clinical sites in St. Petersburg. Participants in Uganda were recruited from Mbarara Regional Referral Hospital from 2011 to 2014 with documented HIV infection via rapid diagnostic testing and recorded ART-naïve in the clinic database. HIV viral load testing of baseline samples was performed; the lower limit of detection was 500 copies/mL in Russia and 40 in Uganda. Due to an unexpectedly high proportion of participants with undetectable viremia, additional tests were performed: enzyme-linked immunosorbent assay HIV testing and testing for ART.

Results: In Russia, 16% (58/360) had undetectable viremia; 3% (9/360) re-tested HIV-seronegative and 4% (13/360) tested positive for ART. In Uganda 11% (55/482) had undetectable viremia; 5% (26/482) re-tested HIV-seronegative, while <1% (4/482) tested positive for ART.

Conclusions: In both Russia & Uganda, undetectable viremia was much higher than would be expected for an HIV-infected ART-naïve cohort. Misclassification of study participants was due to misdiagnosis of HIV with rapid diagnostic testing and inaccurate accounting of ART use. Confirmatory HIV testing could improve accuracy of participants meeting entry criteria for HIV infection as might increased scrutiny of medication use in an ART-naïve cohort.     

Unusual sleep experiences and dissociation as mediators between sleep quality and proneness to hallucinations in a nonclinical population sample: a preliminary study

Introduction: The purpose of this study was to examine the relationship of sleep quality to proneness to hallucinations and the mediating role of dissociation and unusual sleep experiences in a nonclinical sample.

Methods: One hundred and seventy-seven participants completed a questionnaire on sleep quality, a dissociative experiences scale, an unusual sleep experiences scale and a hallucination proneness scale.

Results: The results showed a significant positive association between quality of sleep and hallucination proneness, dissociation and unusual sleep experiences, and that dissociation and unusual sleep experiences fully mediated between sleep quality and hallucination proneness.

Conclusions: Our study highlights the importance of variables related to sleep quality and unusual sleep experiences and dissociation in understanding hallucinations, and the importance of taking these variables into consideration in designing intervention directed at reducing distress caused by hallucinations.     

CXCR4-using HIV variants in a cohort of Black men who have sex with men: HIV Prevention Trials Network 061

Objective: To evaluate factors associated with HIV tropism among Black men who have sex with men (MSM) in the United States enrolled in a clinical study (HIV Prevention Trials Network 061).

Methods: HIV tropism was analyzed using a phenotypic assay (Trofile assay, Monogram Biosciences). Samples were analyzed from 43 men who were HIV infected at enrollment and reported either exclusive insertive intercourse or exclusive receptive intercourse; samples were also analyzed from 20 men who were HIV uninfected at enrollment and seroconverted during the study. Clonal analysis of individual viral variants was performed for seroconverters who had dual/mixed (DM) viruses.

Results: DM viruses were detected in samples from 11 (26%) of the 43 HIV-infected men analyzed at the enrollment visit; HIV tropism did not differ between those reporting exclusive insertive vs receptive intercourse. DM viruses were also detected in five (25%) of the 20 seroconverters. DM viruses were associated with lower CD4 cell counts. Seroconverters with DM viruses had dual-tropic viruses only or mixed populations of CCR5- and dual-tropic viruses.

Conclusions: DM viruses were frequently detected among Black MSM in this study, including seroconverters. Further studies are needed to understand factors driving transmission and selection of CXCR4- and dual-tropic viruses among Black MSM.     

Relation of socioeconomic status to overweight and obesity: a large population-based study of Chinese adults

Background: China has been going through significant changes in social and economical aspects and with great socioeconomic disparity in different regions. However, data on the association between socioeconomic status (SES) and obesity are not available in Tianjin, China.

Aim: This study aimed to investigate the association between SES and high adiposity among the adult population in Tianjin.

Subjects and methods: A total of 7351 individuals aged 20–79 were included in this study. Socioeconomic information was collected through an interview following a structured questionnaire. Waist circumference, body weight and height were measured following standard procedures. Overweight and obesity were defined according to the criteria of the Working Group on Obesity in China. Data were analysed using multinomial logistic regression with adjustment for potential confounders.

Results: Stratified analysis showed that higher monthly income and education were related to decreased odds of abdominal overweight/obesity in women, while high education was associated with increased odds of general overweight/obesity in men. Retirement increased the odds of abdominal overweight and obesity and non-manual work was associated with low odds of abdominal obesity in women.

Conclusions: SES was associated with general and abdominal overweight/obesity and sex may play a role in such an association.     

Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials

Background: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials.

Methods: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation.

Results: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit.

Conclusion: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.     

Testing times: identifying puberty in an identified skeletal sample

Background: Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood.

Aim: This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death.

Materials and methods: Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method.

Results: As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15.

Conclusions: Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty.     

Allergen immunotherapy in allergic rhinitis: current use and future trends

Introduction: Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk.

Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT.

New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy.

Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance.

New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.     

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference.

Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations.

Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci.

Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture.

Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.     

Body parameters of Czech breastfed children compared to the Czech references and WHO growth standards

Background: The study concerns the comparison of percentile curves of Czech breastfed children with Czech national references from 1991 and 2001 and WHO growth standards. Growth charts of breastfed children demonstrate different curve shapes, especially in the first months of life. Incorrect interpretation of the growth curve could lead to premature introduction of complementary foods or infant formula.

Aim: The comparison of four body parameters of Czech breastfed children with currently used Czech national references and WHO standards in order to recommend that Czech paediatricians use either Czech references or WHO standards in their practice.

Subjects and methods: Nine hundred and sixty breastfed children were included in the study of length-for-age, head circumference-for-age, weight-for-age and weight-for-length parameters. All percentile curves were compared. Values of the 50th percentile expressed in z-scores based on both Czech references and WHO standards were tested.

Results: The study confirmed results of previous surveys documenting that growth of breastfed children is specific. Nevertheless, percentile curves of growth parameters of Czech breastfed children are closer to Czech references than WHO standards.

Conclusions: The Czech national references fulfil the needs of Czech paediatricians (with pointing to specifics of breastfed child growth) and WHO standards are suitable, especially for international comparison.     

The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines

Context: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently.

Objective: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier.

Method: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y-Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13^®).

Results: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13® where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab.

Conclusion: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function.     

Virologic outcomes in early antiretroviral treatment: HPTN 052

Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure.

Objective: To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052.

Methods: 1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350–550 cells/mm³ at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm³ at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation.

Results: Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure.

Conclusions: Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.