RESUMEN
BACKGROUND: Hepatitis C virus (HCV) is a leading cause of liver-related mortality and morbidity. Despite effective direct acting antivirals and a simplified treatment algorithm, limited access to HCV treatment in vulnerable populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), hinders global elimination. Adapting the evidence-based, simplified HCV treatment algorithm to the organizational and contextual realities of non-traditional clinic settings serving vulnerable populations can help overcome specific barriers to HCV care. The first phase of the Erase Hep C study aimed to identify barriers and facilitators specific to these vulnerable populations to design the site-specific, simplified treatment protocols. METHODS: Forty-two semi-structured qualitative interviews, guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework, were conducted with clinic staff, community-based organizations providing screening and linkage to care, and patients diagnosed with HCV, to identify contextual barriers and facilitators to treatment at a local community health center's Health Care for the Homeless program in Austin, Texas. Audio-recorded interviews were systematically analyzed using thematic analysis informed by the PRISM framework and design thinking, to anchor barriers and facilitators along the HCV care cascade. Findings were fed into human-centered design workshops to co-design, with clinic staff, site-specific, simplified HCV treatment protocols. RESULTS: The specific needs of PEH and PWID patient populations informed barriers and facilitators of HCV care. Barriers included tracking patients who miss critical appointments or labs, medication access and adherence, and patient HCV knowledge. Clinical teams leveraged existing facilitators and incorporated solutions to barriers into clinic workflows to improve care coordination and medication access. Actionable solutions included augmenting existing staff roles, employing HCV care navigation throughout the cascade, and standardizing medication adherence counseling. CONCLUSIONS: Clinic staff identified HCV care facilitators to leverage, and designed actionable solutions to address barriers, to incorporate into site-specific treatment protocols to improve patient HCV outcomes. Methods used to incorporate staff and patient experiential knowledge into the design of contextualized treatment protocols in non-traditional clinic settings could serve as a model for future implementation research. The next phase of the study is protocol implementation and patient enrollment into a single-arm trial to achieve HCV cure.
RESUMEN
BACKGROUND: Hepatitis C virus (HCV) is the leading indication for liver transplantation and liver-related mortality. The development of direct-acting antivirals (DAA) and a simplified treatment algorithm with a > 97% cure rate should make global elimination of HCV an achievable goal. Yet, vulnerable populations with high rates of HCV still have limited access to treatment. By designing locally contextualized site-specific HCV treatment workflows, we aim to cure HCV in vulnerable, high-risk populations, including people experiencing homelessness (PEH) and people who inject drugs (PWID), in Austin, TX, USA. METHODS: Our implementation science study will utilize a qualitative and design thinking approach to characterize patient and systemic barriers and facilitators to HCV treatment in vulnerable, high-risk populations seeking care across seven diverse primary care clinics serving PEHs and PWIDs. Qualitative interviews guided by the Practical, Robust Implementation and Sustainability Model (PRISM) framework will identify barriers and facilitators by leveraging knowledge and experience from both clinic staff and patients. Data synthesized using thematic analysis and design thinking will feed into workshops with clinic stakeholders for idea generation to design site-specific HCV treatment workflows. Providers will be trained on the use of a simplified HCV treatment algorithm with DAAs and clinic staff on the new site-specific HCV treatment workflows. These workflows will be implemented by the seven diverse primary care clinics serving vulnerable, high-risk populations. Implementation and clinical outcomes will be measured using data collected through interviews with staff as well as through medical chart review. DISCUSSION: Our study provides a model of how to contextualize and implement site-specific HCV treatment workflows targeting vulnerable, high-risk populations in other geographic locations. This model can be adopted for future implementation research programs aiming to develop and implement site-specific treatment workflows for vulnerable, high-risk populations and in primary care clinical settings for other disease states beyond just HCV. TRIAL REGISTRATION: Registered on ClinicalTrials.gov on July, 14, 2022. Identifier: NCT05460130 .
RESUMEN
DNA repair via the homologous recombination pathway requires the recombinase RAD51 and, in vertabrates, five RAD51 paralogs. The paralogs form two complexes in solution, a XRCC3/RAD51C heterodimer and a RAD51B/RAD51C/RAD51D/XRCC2 heterotetramer. Mutation of any one of the five paralog genes prevents subnuclear assembly of recombinase at damaged sites and renders cells 30-100 fold sensitive to DNA cross-linking drugs. Phage display was used to isolate peptides that bind the paralog XRCC3. Sequences of binding peptides showed similarity to residues 14-25 of RAD51C protein. Point mutations in this region of RAD51C altered its interaction with both XRCC3 and RAD51B in a two-hybrid system. A synthetic peptide composed of residues 14-25 of RAD51C fused to a membrane transduction sequence [protein transduction domain 4 (PTD4)], inhibited subnuclear assembly of RAD51 recombinase, and sensitized Chinese hamster ovary cells to cisplatin when added to growth medium. These results suggest that residues 14-25 of RAD51C contribute to a "hot spot" used in both XRCC3-RAD51C and RAD51B-RAD51C interactions. Peptide-based inhibition of homologous recombination may prove useful for improving the efficacy of existing cancer therapies.