TB and TB-HIV care for adolescents and young adults

SETTING: Nine high-burden public tuberculosis (TB) clinics in Gaborone, Botswana. OBJECTIVE: To evaluate the challenges encountered, healthcare worker (HCW) approaches, and supported interventions in TB and TB-HIV (human immunodeficiency virus) care for adolescents and young adults (AYA, aged 10–24 years). DESIGN: Semi-structured interviews with HCW in TB clinics, analyzed using thematic analysis. RESULTS: Sixteen HCWs were interviewed. AYA developmental needs included reliance on family support for care, increasing autonomy, attending school or work, building trust in HCWs, and intensive TB education and adherence support. Stigma strongly influenced care engagement, including clinic attendance and HIV testing. Health system barriers to optimal AYA TB care included limited staffing and resources to follow-up or support. HCWs utilized intensive education and counseling, and transitioned AYA to community-based directly observed therapy whenever feasible. HCWs supported implementation of youth-friendly services, such as AYA-friendly spaces or clinic days, training in AYA care, use of mobile applications, and peer support interventions, in addition to health system strengthening. CONCLUSION: HCWs utilize dedicated approaches for AYA with TB, but have limited time and resources for optimal care. They identified several strategies likely to improve care and better retain AYAs in TB treatment. Further work is needed to study interventions to improve AYA TB care and outcomes

Impacts of the COVID-19 pandemic on access to HIV and reproductive health care among women living with HIV (WLHIV) in Western Kenya: A mixed methods analysis

Results: We analyzed 1,402 surveys and 15 in-depth interviews. Many (32%) CL participants reported greater difficulty refilling medications and a minority (14%) reported greater difficulty accessing HIV care during the pandemic. Most (99%) Opt4Mamas participants reported no difficulty refilling medications or accessing HIV/pregnancy care. Among the CL participants, older women were less likely (aOR = 0.95, 95% CI: 0.92–0.98) and women with more children were more likely (aOR = 1.13, 95% CI: 1.00–1.28) to report difficulty refilling medications. Only 2% of CL participants reported greater difficulty managing FP and most (95%) reported no change in likelihood of using FP or desire to get pregnant. Qualitative analysis revealed three major themes: (1) adverse organizational/economic implications of the pandemic, (2) increased importance of pregnancy prevention during the pandemic, and (3) fear of contracting COVID-19

Ethical Aspects of Involving Adolescents in HIV Research: A Systematic Review of the Empiric Literature

Objective: To evaluate the ethics of involving adolescents in HIV research, we conducted a systematic review of the empiric literature. Methods: Electronic databases Ovid Medline, Embase, and CINAHL were systematically searched using controlled vocabulary terms related to ethics, HIV, specified age groups, and empiric research studies. We reviewed titles and abstracts, including studies that collected qualitative or quantitative data, evaluated ethical issues in HIV research, and included adolescents. Studies were appraised for quality, data were extracted, and studies were analyzed using narrative synthesis. Results: We included 41 studies: 24 qualitative, 11 quantitative, 6 mixed methods; 22 from high-income countries (HIC), 18 from low- or middle-income countries (LMIC), and 1 from both HIC and LMIC. Adolescent, parent, and community perspectives assert the benefits of involving minors in HIV research. Participants in LMIC expressed mixed views regarding parental consent requirements and confidentiality, given adolescents' both increasing autonomy and continued need for adult support. In studies in HIC, sexual or gender minority youth would not participate in research if parental consent were required or if there were confidentiality concerns. There was variation in the comprehension of research concepts, but adolescents generally demonstrated good comprehension of informed consent. Informed consent processes can be improved to increase comprehension and study accessibility. Vulnerable participants face complex social barriers that should be considered in study design. Conclusions: Data support the inclusion of adolescents in HIV research. Empiric research can inform consent processes and procedural safeguards to ensure appropriate access

PHF6 - Somatic Mutations and Their Role in Pathophysiology of MDS and AML

Abstract Recently, rare somatic nonsense PHF6 mutations and deletions have been reported in patients with T-ALL, AML and blast crisis CML. Germ line PHF6 mutations have been described in Borjeson−Forssman−Lehmann syndrome (BFLS), a hereditary X-linked disorder characterized by mental retardation and somatic deformities. Patients with BFLS have been also reported to develop leukemia, suggesting PHF6 mutations may predispose to cancer. PHF6 is a highly conserved 41kDa protein showing ubiquitous expression in a variety of tissues, including bone marrow, CD34+ cells and leukocytes. The function and molecular pathogenesis in hematological disorders is unknown. PHF6 has been suggested to be a tumor suppressor gene (TSG) involved in the control of rRNA synthesis. Recent CHIPseq experiments showed that PHF6 binds upstream of the regulatory sequence of RUNX1. In an index case of a young adult female patient with proliferative CMML with dysmorphic features, we have identified remarkable GL mosaicism for PHF6 mutation (p.K44fs), confirmed by deep sequencing of bone marrow, CD3+ cells, spleen and skin tissue. Subsequently, we screened patients with myeloid neoplasms by targeted multi-amplicon sequencing to determine the prevalence and distribution of PHF6 gene alterations. Sequencing results from 1122 cases were analyzed (778 by targeted deep sequencing and 344 by whole exome sequencing). In total, we identified 45 cases with PHF6 mutations, 32 of which were frameshift or nonsense mutations. Previously, PHF6 have been included in screening panels by Haferlach et al., (Leukemia 2014) and Papaemmanuil et al., (Blood 2013) and somatic mutations were found in 24/944 and 21/738 cases of MDS, respectively. The somatic nature of these defects was confirmed by analysis of non-clonal CD3+ lymphocytes, Thus the incidence of PHF6 mutations ranges from 4.3% in current study to 2.8% and 2.5% reported by others and are most frequently observed among patients with secondary AML (33%), suggesting that PHF6 mutations are not uncommon driver events in myeloid neoplasia. Gender distribution showed a strong male predominance (76%), indicating that retention of a single copy of PHF6 may be protective. There was no significant sex difference in the transcriptional expression of PHF6 itself. The most frequent chromosomal aberration observed in conjunction with PHF6 mutations was trisomy-8 (p=.08). The most commonly associated somatic mutations were in RUNX1 (p=.001) and IDH2 (p=.008). Concomitant PHF6 and RUNX1 mutations are associated with a poor prognosis in AML, and occur predominantly in males. There was no association observed between low expressors of PHF6 and RUNX1 mutations or RUNX1 expression levels. Conversely, RUNX1 mutant cases without somatic PHF6 mutations were not observed to have low transcriptional PHF6 levels. Subsequent analysis of clonal architecture using variant allelic frequency calculations and serial sampling suggested that mutated PHF6 may function as a founder driver gene in proportion of cases, while RUNX1 mutations are acquired as secondary events. Recent studies proposed that PHF6 deficiency leads to impaired cell proliferation, cell cycle arrest at the G2/M phase and an increase in DNA damage. To delineate a possible pathophysiological pathway involving PHF6 we compared transcriptional expression profiles of low expressors to those with normal levels of PHF6. The most notably deregulated group of genes were clustered to a functionally related group of ribosomal RNA proteins (p<.00001). To better understand functional properties of PHF6 we conducted PHF6 specific immuno-precipitation followed by mass spectrometric fingerprinting on K562 cells to identify protein partners. We have identified a novel association of PHF6 in RNA degradation/stability and ribosomal proteins, including MOV and PABPC families. In conclusion, our results indicate that PHF6 mutations are generally present in more aggressive types of myeloid neoplasms and arefrequently associated with RUNX1/IDH2 mutations. Our functional in vitro studies, along with recently published reports, suggest an association of PHF6 deficiency with transcriptional regulation and thereby provide a basis for a transcriptional repressor phenotype conveyed by ancestral lesions, consistent with a role for PHF6 as a TSG. Disclosures Levine: Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees