Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

Background: Cystic Fibrosis causing mutations in the gene CFTR , reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. Methods: A novel small molecule potentiator (SK-POT1), previously identified in CFTR binding studies, was tested for its activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. Results: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. Conclusion: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review.

INTRODUCTION: Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV. METHODS: We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years. RESULTS AND DISCUSSION: Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks. CONCLUSIONS: Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review.

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.

Safety and efficacy of abacavir for treating infants, children, and adolescents living with HIV: a systematic review and meta-analysis.

BACKGROUND: Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations. METHODS: In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230). FINDINGS: Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I2=85%; p<0·0001). The incidence of death (reported in seven studies) following abacavir treatment varied from 0·00% to 5·49% (I2=58%; p=0·026). Viral suppression (<400 copies per mL) varied from 50% to 70% at 6 months (I2=92%, p<0·0001) and from 57% to 78% at 12 months (I2=88%, p<0·0001). INTERPRETATION: Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV. FUNDING: WHO.

Advancing the prevention and treatment of HIV in children: priorities for research and development.

Safe and effective paediatric formulations of the most promising antiretroviral drugs are crucial to advance the treatment and prevention of HIV in neonates, infants, children, and adolescents. The WHO Paediatric Drug Optimization for HIV (PADO-HIV) group brings together stakeholders and experts every 2-3 years to identify priority products and define research gaps in the development of new HIV drugs and formulations for children in low-income and middle-income countries. PADO-HIV 5 met from Sept 27 to Oct 15, 2021. The group evaluated HIV agents from known and novel drug classes, oral and parenteral long-acting formulations, and developments in broadly neutralising antibodies, and included focused sessions on neonates and new delivery technologies. A list of medium-term and long-term priorities was generated, and research questions were defined. This forward-looking analysis is intended to provide guidance to funders, drug developers, and researchers, and to accelerate access for children to the best HIV drugs and formulations.

Effectiveness and Safety of Atazanavir Use for the Treatment of Children and Adolescents Living With HIV: A Systematic Review.

Background: Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents. Methods: We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals. Results: Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15-22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3-4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months. Conclusion: Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3-4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen. PROSPERO number: CRD42022309230.

Prioritising the most needed paediatric antiretroviral formulations: the PADO4 list.

Despite considerable progress in paediatric HIV treatment and timely revision of global policies recommending the use of more effective and tolerable antiretroviral regimens, optimal antiretroviral formulations for infants, children, and adolescents remain limited. The Paediatric Antiretroviral Drug Optimization group reviews medium-term and long-term priorities for antiretroviral drug development to guide industry and other stakeholders on formulations most needed for low-income and middle-income countries. The group convened in December, 2018, to assess progress since the previous meeting and update the list of priority formulations. Issues relating to drug optimisation for neonatal prophylaxis and paediatric treatment, and those relating to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women were also discussed. Continued focus on identifying, prioritising, and providing access to optimal antiretroviral formulations suitable for infants, children, and adolescents is key to ensuring that global HIV treatment targets can be met.

Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities.

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.

Stillbirth in Women Living With HIV Delivering in the United Kingdom and Ireland: 2007-2015.

BACKGROUND: Women living with HIV have a higher risk of adverse birth outcomes, but questions remain regarding their specific risk factors for stillbirth and the extent to which maternal HIV is associated with stillbirth. METHODS: Using data on pregnant women with HIV reported within population-based surveillance in the United Kingdom/Ireland, we described stillbirth rates in 2007-2015 stratified by type of antiretroviral therapy (ART) and evaluated risk factors using Poisson regression. General population stillbirth rates by maternal world region of origin were derived from national annual birth statistics, and compared with rates in women with HIV, using standardized stillbirth ratios with the general population as the reference. RESULTS: Between 2007 and 2015, there were 10,434 singleton deliveries in 8090 women with HIV; 75% of pregnancies were in women of African origin; and 49% were conceived on ART. The stillbirth rate was 8.5 (95% confidence interval: 6.9 to 10.5) per 1000 births. Risk factors for stillbirth included pre-eclampsia, diabetes, Asian maternal origin (versus United Kingdom/Ireland), CD4 count <350 cells/mm, older maternal age, and primiparity. Conceiving on ART did not increase the risk. The stillbirth rates (per 1000 births) by type of ART were 14.3, 11.7, 8.3, and 6.0, respectively for NVP + XTC/TDF-, LPV/r + 3TC/ZDV-, NVP + XTC/ABC-, and NVP + XTC/ZDV-exposed pregnancies (P value = 0.40). The standardized stillbirth ratio was 129 (95% confidence interval: 101 to 165) in women with HIV compared with the general population. CONCLUSION: After adjusting for maternal origin, the stillbirth rate remained higher in women with HIV than the general population. We recommend further studies to understand and prevent this excess.

Diabetes Disparities and Promising Interventions to Address Diabetes in Native Hawaiian and Pacific Islander Populations.

PURPOSE OF REVIEW: The Native Hawaiian and Pacific Islander (NHPI) population is rapidly growing in the USA. NHPIs face significant health disparities and have a high prevalence of diabetes compared to the general US population. RECENT FINDINGS: Recent culturally-adapted diabetes interventions have shown promise in addressing these disparities among NHPI communities. The interventions showed success by utilizing a community-based approach that honored NHPIs' collectivist culture, addressed social determinants of health that influence disease control and prevention, and utilized NHPI community health workers (CHWs) and peer educators for key roles in implementation of the intervention. To address health disparities in the NHPI community, much can be learned from existing, successful interventions. Promising interventions share several attributes. The interventions were: culturally adapted using a community-based participatory research approach; addressed specific social determinants of health (i.e., cost of healthy food, transportation, access to health care) that influence disease control and prevention; honored the collectivist culture of NHPI communities by integrating social networks and extended family members; and utilized NHPI community members, including peer educators and CHWs, for intervention implementation. Further investment to scale these interventions for regional and national implementation is needed to address the significant diabetes disparities that NHPIs face.

Importance of Prospective Studies in Pregnant and Breastfeeding Women Living With Human Immunodeficiency Virus.

Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3-5 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy.

Discovery and electrophysiological characterization of SKF-32802: A novel hERG agonist found through a large-scale structural similarity search.

Despite the importance of the hERG channel in drug discovery and the sizable number of antagonist molecules discovered, only a few hERG agonists have been discovered. Here we report a novel hERG agonist; SKF-32802 and a structural analog of the agonist NS3623, SB-335573. These were discovered through a similarity search of published hERG agonists. SKF-32802 incorporates an amide linker rather than NS3623's urea, resulting in a compound with a different mechanism of action. We find that both compounds decrease the time constant of open channel kinetics, increase the amplitude of the envelope of tails assay, mildly increased the amplitude of the IV curve, bind the hERG channel in either open or closed states, increase the plateau of the voltage dependence of activation and modulate the effects of the hERG antagonist, quinidine. Neither compound affects inactivation nor deactivation kinetics, a property unique among hERG agonists. Additionally, SKF-32802 induces a leftward shift in the voltage dependence of activation. Our structural models show that both compounds make strong bridging interactions with multiple channel subunits and are stabilized by internal hydrogen bonding similar to NS3623, PD-307243 and RPR26024. While SB-335573 binds in a nearly identical fashion as NS3623, SKF-32802 makes an additional hydrogen bond with neighboring threonine 623. In summary, SB-335573 is a type 4 agonist which increases open channel probability while SKF-32802 is a type 3 agonist which induces a leftward shift in the voltage dependence of activation.

Protease inhibitors and preterm delivery: another piece in the puzzle.

BACKGROUND: Questions remain regarding preterm delivery (PTD) risk in HIV-infected women on antiretroviral therapy (ART), including the role of ritonavir (RTV)-boosted protease inhibitors, timing of ART initiation and immune status. METHODS: We examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood on women with HIV delivering a singleton live infant in 2007-2015, including those pregnancies receiving RTV-boosted protease inhibitor-based (n = 4184) or nonnucleoside reverse transcriptase inhibitors-based regimens (n = 1889). We conducted logistic regression analysis adjusted for risk factors associated with PTD and stratified by ART at conception and CD4 cell count to minimize bias by indication for treatment and to assess whether PTD risk differs by ART class and specific drug combinations. RESULTS: Among women conceiving on ART, lopinavir/RTV was associated with increased PTD risk in those with CD4 cell count 350 cells/µl or less [odds ratio 1.99 (1.02, 3.85)] and with CD4 cell count more than 350 cells/µl [odds ratio 1.61 (1.07, 2.43)] vs. women on nonnucleoside reverse transcriptase inhibitors-based (mainly efavirenz and nevirapine) regimens in the same CD4 subgroup. Associations between other protease inhibitor-based regimens (mainly atazanavir and darunavir) and PTD risk were complex. Overall, PTD risk was higher in women who conceived on ART, had low CD4 cell count and were older. No trend of association of PTD with tenofovir or any specific drug combinations was observed. CONCLUSION: Our data support a link between the initiation of RTV-boosted/lopinavir-based ART preconception and PTD in subsequent pregnancies, with implications for treatment guidelines. Continued monitoring of PTD risk is needed as increasing numbers of pregnancies are conceived on new drugs.

The PILI@Work Program: a translation of the diabetes prevention program to Native Hawaiian-serving worksites in Hawai'i.

A previously translated Diabetes Prevention Program Lifestyle Intervention (DPP-LI) was adapted for delivery as a worksite-based intervention, called PILI@Work, to address obesity disparities in Native Hawaiians/Pacific Islanders. This study examined the effectiveness of PILI@Work and factors associated with weight loss at post-intervention. Overweight/obese employees of 15 Native Hawaiian-serving organizations received the 3-month component of PILI@Work. Assessments included weight, systolic/diastolic blood pressure, physical activity and functioning, fat intake, locus of weight control, social support, and self-efficacy. Weight, systolic/diastolic blood pressure, physical functioning, physical activity frequency, fat intake, family support, and eating self-efficacy improved from pre- to post-intervention. Regression analysis indicated that worksite type, decreased diastolic blood pressure, increased physical activity, and more internalized locus of weight control were significantly associated with 3-month weight loss. PILI@Work initiated weight loss in Native Hawaiians/Pacific Islanders. DPP-LI translated to worksite settings and tailored for specific populations can be effective for addressing obesity.

Prevalence of depressive symptoms in pregnant and postnatal HIV-positive women in Ukraine: a cross-sectional survey.

BACKGROUND: Perinatal depression among HIV-positive women has negative implications for HIV-related and other maternal and infant outcomes. The aim of this study was to investigate the burden and correlates of perinatal depression among HIV-positive women in Ukraine, a lower middle income country with one of the largest HIV-positive populations in Europe. METHODS: Cross-sectional surveys nested within the Ukraine European Collaborative Study were conducted of HIV-positive women at delivery and between 1 and 12 months postpartum. Depressive symptoms in the previous month were assessed using a self-report screening tool. Other data collected included demographics, antiretroviral therapy (ART)-related self-efficacy, and perceptions of risks/benefits of interventions to prevent mother-to-child transmission (PMTCT). Characteristics of women with and without a positive depression screening test result were compared using Fisher's exact test and χ2 test for categorical variables. RESULTS: A quarter (27% (49/180) antenatally and 25% (57/228) postnatally) of participants screened positive for depressive symptoms. Antenatal risk factors were living alone (58% (7/12) vs. 25% (42/167) p = 0.02), being somewhat/terribly bothered by ART side effects (40% (17/43) vs. 23% (30/129) not /only slightly bothered, p = 0.05) and having lower ART-related self-efficacy (43% (12/28) vs. 23% (25/110) with higher self-efficacy, p = 0.05). Postnatally, single mothers were more likely to screen positive (44% (20/45) vs. 21% (18/84) of cohabiting and 19% (19/99) of married women, p < 0.01) as were those unsure of the effectiveness of neonatal prophylaxis (40% (20/45) vs. 18% (28/154) sure of effectiveness, p < 0.01), those worried that neonatal prophylaxis could harm the baby (30% (44/146) vs. 14% (10/73) not worried p < 0.01) and those not confident to ask for help with taking ART (48% (11/23) vs. 27% (10/37) fairly confident and 15 % (4/26) confident that they could do this). Of women who reported wanting help for their depressive symptoms, 82% (37/45) postnatally but only 31% (12/39) antenatally were already accessing peer counselling, treatment adherence programmes, support groups or social services. CONCLUSIONS: A quarter of women screened positive for depression. Results highlight the need for proactive strategies to identify depressive symptoms, and an unmet need for provision of mental health support in the perinatal period for HIV-positive women in Ukraine.

Community-Based Participatory Research Integrates Behavioral and Biological Research to Achieve Health Equity for Native Hawaiians.

Native Hawaiians bear a disproportionate burden of type-2 diabetes and related complications compared to all other groups in Hawai'i (e.g., Whites, Japanese, Korean). Distrust in these communities is a significant barrier to participation in epigenetic research studies seeking to better understand disease processes. The purpose of this paper is to describe the community-based participatory research (CBPR) approach and research process we employed to integrate behavior and biological sciences with community health priorities. A CBPR approach was used to test a 3-month evidence-based, diabetes self-management intervention (N = 65). To investigate the molecular mechanisms linking inflammation with glucose homeostasis, a subset of participants (n = 16) provided peripheral blood mononuclear cells. Community and academic researchers collaborated on research design, assessment protocols, and participant recruitment, prioritizing participants' convenience and education and strictly limiting the use of the data collected. Preliminary results indicate significant changes in DNA methylation at gene regions associated with inflammation and diabetes signaling pathways and significant improvements in hemoglobin A1c, self-care activities, and diabetes distress and understanding. This study integrates community, behavioral, and epigenomic expertise to better understand the outcomes of a diabetes self-management intervention. Key lessons learned suggest the studies requiring biospecimen collection in indigenous populations require community trust of the researchers, mutual benefits for the community and researchers, and for the researchers to prioritize the community's needs. CBPR may be an important tool in providing communities the voice and protections to participate in studies requiring biospecimens.

Pregnancy outcomes in HIV-positive women in Ukraine, 2000-12 (European Collaborative Study in EuroCoord): an observational cohort study.

BACKGROUND: Women living with HIV are potentially at increased risk of adverse pregnancy outcomes, due to a range of factors, including immunosuppression, use of combination antiretroviral therapy (ART), and injecting drug use. Rates of mother-to-child transmission of HIV in Ukraine have declined to around 2-4%, but little is known about other pregnancy outcomes in this setting. We used data from an observational prospective cohort study to assess pregnancy outcomes among HIV-positive women in Ukraine. METHODS: The European Collaborative Study (ECS) in EuroCoord is a continuing cohort study, established in Ukraine in 2000. Eligible women are those with a diagnosis of HIV infection before or during pregnancy (including intrapartum) who deliver liveborn babies at seven sites. Maternal sociodemographic, HIV-related, and delivery (mother and infant) data were collected with study-specific questionnaires. We used Poisson regression models to identify factors associated with preterm delivery (before 37 weeks' gestation) and small weight for gestational age (less than the tenth percentile of weight for gestational age), based on complete cases. FINDINGS: Between January, 2000, and July, 2012, data were collected on 8884 HIV-positive mother and liveborn infant pairs. Median maternal age was 26·5 years (IQR 23·1-30·3). 832 (11%) women had WHO stage 3 or 4 HIV and 1474 (17%) had a history of injecting drug use. 7348 (83%) had received antenatal ART. Among 7435 for whom ART type was available, 4396 (50%) had received zidovudine monotherapy and 2949 (33%) combination ART. Preterm delivery was seen in 780 (9%, 95% CI 8-9) of 8860 births overall and in 77 (9%, 7-11) of 889 babies with small size for gestational age. Factors associated with preterm delivery were history of injecting drug use (adjusted risk ratio 1·64, 95% CI 1·38-1·95), no ART (2·94, 2·43-3·57 vs zidovudine monotherapy), antenatal combination ART (1·40, 1·14-1·73 vs zidovudine monotherapy), WHO stage 4 HIV (2·42, 1·71-3·41 vs WHO stage 1), and being in the most socially deprived group (1·38, 1·11-1·71). Small size for gestational age was associated with history of injecting drug use (adjusted RR 1·39, 95% CI 1·16-1·65), most socially deprived (1·32, 1·09-1·61), no ART (1·60, 1·32-1·94 vs zidovudine monotherapy), and antenatal combination ART (1·33, 1·12-1·60 vs zidovudine monotherapy). INTERPRETATION: Some risk factors for adverse pregnancy outcomes were directly associated with HIV and treatment and others were shared with the general antenatal population. Monitoring of pregnancy outcomes in Ukraine will be important as use of antenatal combination ART increases. FUNDING: European Union Seventh Framework Programme, Wellcome Trust.

The PILI 'Ohana Project: a community-academic partnership to achieve metabolic health equity in Hawai'i.

Native Hawaiians and Pacific Islanders (NHPI) have higher rates of excess body weight and related medical disorders, such as diabetes and cardiovascular disease, compared to other ethnic groups in Hawai'i. To address this metabolic health inequity, the Partnership for Improving Lifestyle Intervention (PILI) 'Ohana Project, a community-academic partnership, was formed over eight years ago and developed two community-placed health promotion programs: the PILI Lifestyle Program (PLP) to address overweight/obesity and the Partners in Care (PIC) to address diabetes self-care. This article describes and reviews the innovations, scientific discoveries, and community capacity built over the last eight years by the PILI 'Ohana Project's (POP) partnership in working toward metabolic health equity. It also briefly describes the plans to disseminate and implement the PLP and PIC in other NHPI communities. Highlighted in this article is how scientific discoveries can have a real-world impact on health disparate populations by integrating community wisdom and academic expertise to achieve social and health equity through research.

Adherence to antiretroviral therapy during pregnancy and the first year postpartum among HIV-positive women in Ukraine.

BACKGROUND: Poor adherence to antiretroviral therapy (ART) is associated with HIV disease progression and, during pregnancy, increased mother-to-child transmission risk. In Ukraine, access to combination ART is expanding but data on adherence are scarce. METHODS: Cross-sectional surveys of HIV-positive women were conducted i) at delivery (on antenatal ART adherence) and ii) during the first year postpartum (on ART adherence in the preceding four weeks). Factors associated with a score ≤ 11 on the self-report Case Adherence Support Evaluation (CASE) index or ≥ 1 self-reported missed dose were assessed using Fisher's exact test. RESULTS: Of 185 antenatal participants and 102 postnatal participants, median ages were 27.5 and 29.5 years respectively: 28% (50/180) and 27% (26/98) reported an unplanned pregnancy, and 13% (24/179) and 17% (17/98) an illicit drug-use history (excluding marijuana). One quarter (49/180 antenatally, 27/101 postnatally) screened positive for depression. The proportion reporting 'low' ART-related self-efficacy (i.e. unable to do ≥ 1/5 ART-taking activities) was 20% (28/141) antenatally and 17% (11/66) postnatally. Antenatally, 14% (95% CI 10-21%) had a CASE score ≤ 11 and 35% (95% CI 28-42%) reported missing ≥ 1 dose. Factors associated with a CASE score ≤ 11 were unplanned pregnancy (25% (12/48) vs. 11% (13/120) where planned, p = 0.03) and living with extended family (23% (13/57) vs. 10% (12/125) living with partner/alone, p = 0.04). Self-report of ≥ 1 missed dose antenatally was additionally associated with younger age (p = 0.03) and lower self-efficacy (50% (14/28) reported ≥ 1 missed dose vs. 28% (30/108) of those with high self-efficacy, p = 0.04). Of 102 postnatal participants, 8% (95% CI 4-15%) had a CASE score ≤ 11 and 31% (95% CI 22-41%) reported ≥ 1 missed dose. Of 11 women with low self-efficacy, 3 (27%) had a CASE score ≤ 11 compared with 3/55 (5%) of those with high self-efficacy (p = 0.05). Current smokers more commonly reported ≥ 1 missed dose postnatally (50% (13/26) vs. 25% (18/72) of non-smokers, p = 0.03). CONCLUSIONS: Our results highlight unmet needs for counselling and support. We identify some groups at risk of poor ART adherence, including women with markers of social vulnerability and those with low ART-related self-efficacy, who may benefit from targeted interventions.