Effect of self-efficacy among persons who inject drugs treated with direct-acting antivirals on Hepatitis C treatment initiation, duration, completion, adherence, and cure.

BACKGROUND: Self-efficacy, a patient-level factor, has been shown to facilitate patient engagement in treatment and optimize treatment-related outcomes in various health contexts. Research on interventions supporting hepatitis C virus (HCV) direct-acting antiviral (DAA) treatment uptake and adherence among persons who inject drugs (PWID) is needed, but whether self-efficacy factors influence DAA treatment cascade outcomes in this population has been less studied. METHODS: Using the HERO study data, we analyzed a subset of participants with any general health self-efficacy data (n=708) measured at baseline and end-of-treatment time points using a 5-items instrument (facets: 'goal setting', 'goal attainment', 'having a positive effect', 'being in control', and 'working to improve'). The cascade outcomes included DAA treatment initiation, duration, adherence, completion, and sustained virologic response (SVR). The effect of baseline and change (Δ) scores for composite and item-level self-efficacy on the cascade outcomes was assessed using logistic regression and generalized linear models. RESULTS: Higher baseline composite self-efficacy [adjusted odds ratio (95 % confidence interval) =1.57 (1.07, 2.29)], 'goal attainment' [1.31 (1.03, 1.67)] and 'having a positive effect' [1.33 (1.03, 1.74)] were associated with greater likelihood of treatment initiation. 'Δ Goal attainment' was significantly associated with SVR [1.63 (1.04, 2.53)]. 'Δ Being in control' and 'Δ working to improve' were associated with treatment adherence and duration, respectively. CONCLUSIONS: General health self-efficacy positively influences DAA treatment initiation among PWID. 'Goal attainment' facilitates the achievement of DAA treatment-related outcomes. Further studies should assess the effect of self-efficacy related to performing healthcare tasks specific to DAAs on the treatment-related outcomes.

Telomeric RNA (TERRA) increases in response to spaceflight and high-altitude climbing.

Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.

The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.

Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

Overreporting of adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs in the HERO study.

BACKGROUND: Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. METHODS: This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. RESULTS: The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs. < 25% overreporting (86.7% vs. 95.8%, p <.001). The factors associated with ≥ 25% Δ adherence were unemployment; higher number of days and times/day of injecting drugs; higher proportion of positive urine drug screening for amphetamine, methamphetamine, and oxycodone, and negative urine screening for THC (tetrahydrocannabinol)/cannabis. CONCLUSIONS: Self-reported DAA adherence was significantly greater than objectively measured adherence among PWID by 19.2%. Having ≥ 25% overreported adherence was associated with optimal prediction of lower SVR rates. PWID with risk factors for high overreporting may need to be more intensively managed to promote actual adherence.

Test characteristics for combining non-invasive liver fibrosis staging modalities in individuals with Hepatitis C virus.

Non-invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow-up. Although individual test characteristics are well-described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis-4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6-98.8%) for FIB-4 to 99.4% (95% CB 99.0-99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3-96.9%, NPV to 99.7-99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non-invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations.

Optimal hepatitis C treatment adherence patterns and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are highly effective for treating HCV infection even among people who inject drugs (PWID). Yet, little is known about patients' adherence patterns and their association with sustained virologic response (SVR) rates. We aimed to summarize various adherence patterns and determine their associations with SVR. METHODS: Electronic blister packs were used to measure daily adherence to once-a-day sofosbuvir/velpatasvir during the 12-week treatment period among active PWIDs. Blister pack data were available for 496 participants who initiated DAAs for whom SVR status was known. Adherence was summarized in multiple patterns, such as total adherent days, consecutive missed days, and early discontinuations. Thresholds for adherence patterns associated with >90% SVR rates were also determined. RESULTS: The overall SVR rate was 92.7%, with a median adherence rate of 75%. All adherence patterns indicating greater adherence were significantly associated with achieving SVR. Participant groups with ≥50% (>42/84) adherent days or <26 consecutive missed days achieved an SVR rate of >90%. Greater total adherent days during 9-12 weeks and no early discontinuation were significantly associated with higher SVR rates only in those with <50% adherence. Participants with first month discontinuation and ≥2 weeks of treatment interruption had low SVR rates, 25% and 85%, respectively. However, greater adherent days were significantly associated with SVR (adjusted odds ratio 1.10; 95% CI 1.04-1.16; p <0.001) even among participants with ≥14 consecutive missed days. CONCLUSIONS: High SVR rates can be achieved in the PWID population despite suboptimal adherence. Encouraging patients to take as much medication as possible, with <2 weeks consecutive missed days and without early discontinuation, was found to be important for achieving SVR. IMPACT AND IMPLICATIONS: People who inject drugs can be cured of HCV in >90% of cases, even with relatively low adherence to direct-acting antivirals, but early discontinuations and long treatment interruptions can significantly reduce the likelihood of achieving cure. Clinicians should encourage people who inject drugs who are living with HCV to adhere daily to direct-acting antivirals as consistently as possible, but if any days are interrupted, to continue and complete treatment. These results from the HERO study are important for patients living with HCV, clinicians, experts writing clinical guidelines, and payers. CLINICAL TRIAL NUMBER: NCT02824640.

Evaluation of intervention components to maximize yoga practice among people with chronic pain taking opioid agonist therapy: A factorial experiment using the multiphase optimization strategy framework.

BACKGROUND: Chronic pain affects up to half of individuals taking opioid agonist therapy (OAT; i.e., methadone and buprenorphine) for opioid use disorder (OUD), and yoga-based interventions may be useful for decreasing pain-related disability. Whereas more yoga practice (i.e., higher "dosage") may improve pain-related outcomes, it can be challenging for people with chronic pain taking OAT to attend class regularly and sustain a regular personal yoga practice. Therefore, we plan to optimize a yoga-based intervention (YBI) package in order to support class attendance and personal practice, thus maximizing the yoga dose received. STUDY DESIGN: Using the Multiphase Optimization Strategy (MOST) framework, we will conduct a factorial experiment to examine four intervention components that may be added to a weekly yoga class as part of a YBI. Components include: 1) personal practice videos featuring study yoga teachers, 2) two private sessions with a yoga teacher, 3) daily text messages to inspire personal practice, and 4) monetary incentives for class attendance. The primary outcome will be minutes per week engaged in yoga (including class attendance and personal practice). We plan to enroll 192 adults with chronic pain who are taking OAT for OUD in this 2x2x2x2 factorial experiment. CONCLUSION: Results of the study will guide development of an optimized yoga-based intervention package that maximizes dosage of yoga received. The final treatment package can be tested in a multisite efficacy trial of yoga to reduce pain interference in daily functioning in people with chronic pain who are taking OAT. TRIAL REGISTRATION: Pre-registration of the study was completed on ClinicalTrials.gov (identifier: NCT04641221).

Self-reported and measured adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND: Objective adherence measures, such as electronic blister pack (BP), for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment have high accuracy, but their use is limited in real practice settings. We examined the association of self-reported adherence using a visual analogue scale (VAS) with objective BP adherence and sustained virologic response (SVR) among people who inject drugs. METHODS: We conducted secondary analyses using a subset of participants (N = 493) from the per-protocol sample of the HERO study, a pragmatic randomized trial of HCV treatment interventions that used both VAS and BP to measure adherence to a 12-week sofosbuvir/velpatasvir DAA regimen. Multivariable mixed-effects regression models tested the association of self-report adherence level with longitudinal weekly objective adherence. Multivariable logistic regression tested the association of self-report adherence with SVR. RESULTS: The average VAS and BP adherences were 95.1 % (SD = 8.9 %) and 76.0 % (16.0 %), respectively, and the proportion of the participants achieving SVR was 92.9 %. The estimated adjusted mean objective adherence was significantly different (-16 %; 95 % CI: -22 %, -11 %, p < .001) between participants with 100 % and <80 % VAS adherence. The likelihood of SVR was significantly lower for those with <80 % VAS adherence [adjusted OR = 0.07; 95 % CI: 0.02, 0.24; p < .001] compared to those with 100 %. CONCLUSION: Self-reported adherence overestimated objective adherence. However, higher self-report adherence was significantly associated with higher objective adherence. Also, self-reported adherence ≥80 % was significantly associated with SVR. Thus, the self-report measure has utility as a monitoring tool for adherence during DAA treatment.

Shame and stigma in association with the HCV cascade to cure among people who inject drugs.

BACKGROUND: Psycho-social experiences including shame and experienced and internalized stigma have been associated with substance use, HCV infection, and reluctance to disclose HCV status and pursue treatment. These psycho-social barriers have been examined independently for many chronic diseases, including HCV, but to our knowledge have not been quantitatively explored in a large multi-site US-based sample of people who inject drugs (PWID) in HCV treatment. METHODS: We examine baseline relationships with HCV-stigma and engagement across the HCV treatment cascade as well as baseline and longitudinal relationships between shame and engagement across the HCV treatment cascade including treatment initiation, adherence, completion, and sustained virologic response (SVR) among a multi-site sample of PWID with HCV, where N=755 were randomized to the pragmatic trial comparing HCV treatment outcomes in modified directly observed treatment (mDOT) or patient navigation, and N=623 initiated treatment. RESULTS: While cross-sectional assessments of shame and HCV-stigma were not associated with engagement across the HCV treatment cascade, those whose shame scores decreased compared to those who reported consistently high and increasing levels of shame were significantly more likely to complete HCV treatment (aOR=5.29; 95%CI: 1.56,18.00) and achieve SVR (aOR=6.32; 95%CI: 1.61, 24.87). CONCLUSION: Results underscore the relationships between lower levels of shame and health-related behavior and treatment outcomes among PWID and suggest SVR achievement may contribute to reductions in shame or that reductions in shame may contribute to continued treatment and thus SVR.

Reduction in Depressive Symptoms in People who Inject Drugs who Are Cured of Hepatitis C Virus Infection: The HERO Study.

Background: Depressive symptoms are prevalent among people who inject drugs (PWID) and people with hepatitis C virus (HCV). We examined changes in depressive symptoms among HCV-infected PWID following direct-acting antiviral treatments to evaluate whether these changes differed by history of depressive symptoms, substance use, or HCV treatment outcome. Methods: We conducted a secondary analysis of the HERO Study (NCT02824640), a pragmatic randomized clinical trial among PWID, to test the effectiveness of HCV care models. Depressive symptoms (primary outcome) were measured using the Patient Health Questionnaire (PHQ-9) at baseline, end of treatment (EOT), and at follow-up 12 and 24 weeks after EOT. Sustained virologic response (SVR) was defined as undetectable HCV RNA at ≥12 weeks following EOT. Baseline drug use was defined as having a positive urine screening test for amphetamine, methamphetamine, benzodiazepine, cocaine, cannabis, opiate, or oxycodone. Results: The sample (n = 498) was 72.3% male, 64.2% White, and on average 43.9 years old. In patients who achieved SVR (F(3432) = 4.58; P = .004) and those with drug use at baseline (F(3478) = 5.11; P < .01), PHQ-9 scores significantly declined over time, with scores lower at EOT and both follow-ups as compared with baseline. Mean PHQ-9 scores at EOT and follow-ups were significantly lower than at baseline, except for those with no depression or mild depression at baseline. Conclusions: This study showed that HCV treatment in PWID is associated with sustained declines in depression up to 24 weeks post-treatment among those who achieve SVR and that drug use does not interfere with improvement in depressive symptoms.

A Video-Observed Treatment Strategy to Improve Adherence to Treatment Among Persons Who Inject Drugs Infected With Hepatitis C Virus: Qualitative Study of Stakeholder Perceptions and Experiences.

BACKGROUND: Direct-acting antiviral medications have the potential to eliminate the hepatitis C virus (HCV) epidemic among people who inject drugs; yet, suboptimal adherence remains a barrier. Directly observed treatment (DOT), an effective strategy for optimizing adherence, has been frequently implemented in opioid treatment programs but less commonly in community health settings due to the heavy burden of daily visits. An alternative is video-observed therapy (VOT), which uses mobile health technology to monitor adherence. VOT has not been widely studied among people who inject drugs with HCV. OBJECTIVE: This qualitative study, part of a larger implementation evaluation, investigates stakeholder perceptions and experiences with VOT in Project HERO (Hepatitis C Real Outcomes), a multisite pragmatic trial testing treatment delivery models for people who inject drugs with HCV. Our goal was to understand the potential barriers and facilitators to the implementation of the VOT technology. METHODS: Qualitative interviews were conducted with 27 Project HERO study staff and 7 patients. Interviews focused on perceptions and experiences with the VOT app and barriers and facilitators to implementation. Team meeting minutes over the first 2 years of the project were transcribed. A coding system was developed and applied to the data. We summarized thematic data and compared participant perceptions to generate a close understanding of the data. RESULTS: Frequent barriers to VOT included mechanical failure, stolen or lost phones, and a steep learning curve for participants and study staff. In sites with older and less technically skilled participants, staff found it difficult to implement the VOT app. Research staff found that the routine monitoring of app use led to closer engagement with participants. This was both a benefit and a potential threat to the validity of this pragmatic trial. Patient participants reported mixed experiences. CONCLUSIONS: VOT may be a useful alternative to DOT for some patients, but it may not be feasible for all. Significant staff involvement may be required.

Injecting practices during and after hepatitis C treatment and associations with not achieving cure among persons who inject drugs.

BACKGROUND: Persons who inject drugs (PWID) are a key population for hepatitis C virus (HCV) treatment. Study aims were to describe injection practices of PWID during HCV treatment with direct-acting antivirals (DAAs) and assess whether injection practices were associated with not achieving a sustained virologic response (SVR). METHODS: Secondary analysis of the HERO Study (ClinicalTrials.gov, NCT02824640), a pragmatic randomized trial in 8 U.S. states to evaluate the effectiveness of HCV care models among active PWID seen in opioid treatment programs and community clinics. Frequency, sharing and reuse of injecting equipment were assessed at baseline, end-of-treatment (EOT) and quarterly visits up to 60 weeks post-treatment. Generalized Estimating Equations logistic regression models with linear spline were used to compare trends in injecting behaviors during vs. post-treatment. Multivariable logistic regression models explored associations between injecting behaviors during treatment and lack of SVR. RESULTS: Among 501 participants, 27% were female, 35% were non-white, mean age was 44 (SD 11.5) years and nearly half (49%) were unhoused. At baseline, 41% reported receptive sharing of injecting equipment, declining to 16% at EOT visit. Receptive sharing of cookers, rinses, or needles/syringes during treatment was associated with a nearly 5-fold increase in not achieving SVR (adjusted odds ratio (aOR)=4.83; 95% CI: 2.26, 10.28) as was reuse of one's own needles/syringes (aOR=2.37; 95% CI: 1.11, 4.92). CONCLUSIONS: PWID in the HERO study adopted safer injecting behaviors during DAA treatment; receptive sharing of injecting equipment and reuse of one's own equipment during treatment were associated with not achieving cure.

The experience of re-infection among people who inject drugs successfully treated for hepatitis C.

INTRODUCTION: Highly effective direct-acting antiviral (DAA) agents have changed the landscape of hepatitis C virus infection (HCV) treatment and have become more available to people who inject drugs (PWID) over the past several years. Although many achieve a sustained virologic response (SVR), a small proportion will become re-infected. This study examined experiences of re-infection among participants in Project HERO, a large multi-site treatment trial designed to test alternative treatment delivery models for DAAs. METHODS: Study staff conducted qualitative interviews with twenty-three HERO participants who experienced reinfection following successful treatment for HCV. Interviews focused on life circumstances and experiences with treatment/re-infection. We conducted a thematic analysis, followed by a narrative analysis. RESULTS: Participants described challenging life circumstances. The initial experience of cure was joyful, leading participants to feel that they had escaped a defiled, stigmatized identity. Re-infection was very painful. Feelings of shame were common. Participants with fully developed narratives of re-infection described both a strong emotional response as well as a plan for avoiding re-infection during retreatment. Participants who lack such stories showed signs of hopelessness and apathy. CONCLUSION: Though the promise of personal transformation through SVR may be motivating for patients, clinicians should be cautious about how they describe the "cure" when educating patients about HCV treatment. Patients should be encouraged to avoid stigmatizing, dichotomizing language of the self, including terms such as "dirty" and "clean." In acknowledging the benefits of HCV cure, clinicians should emphasize that re-infection does not mean failed treatment; and that current treatment guidelines support retreatment of re-infected PWID.

The effect of antiretroviral therapy with high central nervous system penetration on HIV-related cognitive impairment: a systematic review and meta-analysis.

Chronic complications are a significant concern for people living with HIV/AIDS (PLWHA) infection. HIV-associated neurocognitive disorders (HAND) are prevalent in PLWHA. Yet, the efficacy of medications that penetrate the central nervous system (CNS) at preventing or slowing the progression of HAND remains largely unknown. The objective of this study was to determine whether high CNS penetration effectiveness (CPE) regimens improve neurocognitive test scores in PLWHA on combined antiretroviral therapy (cART). Primary literature evaluating cognitive outcomes based on CPE score of cART regimens in PLWHA was assembled from PubMed/Medline and EMBASE. Both randomized controlled trials and observational studies with at least 12 weeks of follow-up were included. A meta-analysis was conducted to calculate the standardized mean difference. Eight trials including a total of 3,303 patients with 13,103 person-years of follow-up were included in the systematic review. Four trials (n = 366 patients) met our inclusion criteria and were included in the meta-analysis. In the meta-analysis, HIV regimens with a high CPE score did not affect NPZ-4 or GDS scores (standardized mean difference (SMD) 0.10, 95% CI -0.19, 0.38; I2 = 26%). Future studies with larger sample sizes are warranted to prospectively evaluate the relationship between CPE and progression of HAND.

Patient-centred models of hepatitis C treatment for people who inject drugs: a multicentre, pragmatic randomised trial.

BACKGROUND: To achieve WHO targets for the elimination of hepatitis C virus (HCV) as a public threat, an increased uptake of HCV treatment among people who inject drugs (PWID) is urgently needed. Optimal HCV co-located treatment models for PWID have not yet been identified. We aimed to compare two patient-centred models of HCV care in PWID with active drug use. METHODS: We did a pragmatic randomised controlled trial at eight US cities in eight opioid treatment programmes and 15 community health centres. PWID actively injecting within 90 days of study entry were randomly assigned (1:1) to either patient navigation or modified directly observed therapy (mDOT) using computer-generated variable block sizes of 2-6 stratified by city, clinical settings, and cirrhosis status. The randomisation code was concealed, in a centralised REDCap database platform, from all investigators and research staff except for an authorised data manager at the data coordinating centre. All participants received a fixed-dose combination tablet (sofosbuvir 400 mg plus velpatasvir 100 mg) orally once daily for 12 weeks. The primary outcome was sustained virological response (SVR; determined by chart review between 70 days and 365 days after end of treatment and if unavailable, by study blood draws), and secondary outcomes were treatment initiation, adherence (measured by electronic blister packs), and treatment completion. Analyses were conducted within the modified intention-to-treat (mITT; all who initiated treatment), intention-to-treat (all who were randomised), and per-protocol populations. This trial is registered with ClinicalTrials.gov, NCT02824640. FINDINGS: Between Sept 15, 2016, and Aug 14, 2018, 1891 individuals were screened and 1136 were excluded (213 declined to participate and 923 did not meet the eligibility criteria). We randomly assigned 755 participants to patient navigation (n=379) or mDOT (n=376). In the mITT sample of participants who were randomised and initiated treatment (n=623), 226 (74% [95% CI 69-79]) of 306 participants in the mDOT group and 236 (76% [69-79]) of 317 in the patient navigation group had an SVR, with no significant difference between the groups (adjusted odds ratio [AOR] 0·97 [95% CI 0·66-1·42]; p=0·35). In the ITT sample (n=755), 226 (60% [95% CI 55-65]) of 376 participants in the mDOT group and 236 (62% [57-67]) of 379 in the patient navigation group had an SVR (AOR 0·92 [0·68-1·25]; p=0·61) and in the per-protocol sample (n=501), 226 (91% [87-94]) of 248 participants in the mDOT group and 235 (93% [89-96]) of 253 in the patient navigation group had an SVR (AOR 0·79 [0·41-1·55]; p=0·44). 306 (81%) of 376 participants in the mDOT group and 317 (84%) of 379 participants in the patient navigation group initiated treatment (AOR 0·86 [0·58-1·26]; p=0·44) and, among those, 251 (82%) participants in the mDOT group and 264 (83%) participants in the patient navigation group completed treatment (AOR 0·90 [0·58-1·39]; p=0·63). Mean daily adherence was higher in the mDOT group (78% [95% CI 75-81]) versus the patient navigation group (73% [70-77]), with a difference of 4·7% ([1·9-7·4]; p=0·0010). 421 serious adverse events were reported (217 in the mDOT group and 204 in the patient navigation group), with the most common being hospital admission (176 in the mDOT group vs 161 in the patient navigation group). INTERPRETATION: In this trial of active PWID, both models resulted in high SVR. Although adherence was significantly higher in the mDOT group versus the patient navigation group, there was no significant difference in SVR between the groups. Increases in adherence and treatment completion were associated with an increased likelihood of SVR. These results suggest that active PWID can reach high SVRs in diverse settings with either mDOT or patient navigation support. FUNDING: Patient-Centered Outcomes Research Institute, Gilead Sciences, Quest Diagnostics, Monogram Biosciences, and OraSure Technologies.

Treatment for hepatitis C virus with direct acting antiviral agents: Perspectives and treatment experiences of people who inject drugs.

INTRODUCTION: Increasingly, people who inject drugs (PWID) infected with hepatitis C virus (HCV) are gaining access to highly effective direct-acting antiviral agents (DAAs). Although past studies examined patient experiences with interferon-based treatments, few have explored patient experiences with these new generation therapeutics. Research and real world experience indicate that many PWID can be successfully treated with the new DAAs. Yet a substantial minority fail to complete treatment or achieve only suboptimal adherence. This qualitative study examines experiences with treatment among participants in Project HERO, a large multisite trial designed to compare treatment delivery methods for DAAs. We explored treatment experiences among HERO participants, with the goal of understanding potential barriers to treatment engagement and completion. METHODS: We conducted qualitative interviews with a sample of 21 participants, including 14 who completed HCV treatment and 7 participants who discontinued treatment before the end of the 12-week medication course. The first phase of the analysis was descriptive, examining participants' life experiences, histories of disease and treatment seeking, experiences with the program, and barriers to treatment completion. The second phase of the analysis examined differences between completers and noncompleters. RESULTS: Participants offered a variety of reasons for seeking treatment. Both groups of participants reported highly positive experiences of the HERO trial. Participants described research staff as caring, respectful, and nonjudgmental. Substance use was reported by both groups, yet completers described "manageable" substance use, while noncompleters described substance use that sapped their energy and motivation. Shame over drug use was a barrier to treatment completion. Homelessness and a reported lack of social support were much more common in the noncompleter group. CONCLUSIONS: Reasons for noncompletion were not related to features of the clinical trial or treatment program. Our results indicate the importance of: 1) recognizing and addressing severe social and economic challenges such as homelessness; and 2) building a program culture of respect and compassion in treatment programs for PWID infected with HCV.

Ad Astra - telomeres in space!

PURPOSE: My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavor to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars. CONCLUSIONS: Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55 years) on short duration missions (less than 20 days). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.