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Background: Doxycycline post-exposure prophylaxis (doxy-PEP) reduces chlamydia, gonorrhea, and syphilis infections among men who have sex with men (MSM) and transwomen (TW). Perspectives of health care providers (HCPs) regarding doxy-PEP can inform implementation efforts., Methods: From August 2022 to January 2023, HCPs were recruited from 13 cities with high sexually transmitted infection (STI) rates for semi-structured, in-depth interviews about their awareness of and attitudes towards doxy-PEP for STI prevention. HCPs were purposively sampled to include people with experience prescribing PrEP and provision of care to MSM. Interviews were conducted virtually via Zoom. Transcripts and debrief reports were analyzed using a directed content analysis approach to explore knowledge, attitudes, and beliefs about doxy-PEP., Results: Among 30 HCPs, almost half (47%) were between 31-40 years of age, 53% identified as male, and 47% reported their sexual orientation as gay or queer. Half (53%) of participants practiced in the South, 43% had >100 MSM in their clinic panel, and 17% had previously prescribed doxy-PEP. We identified four overarching themes: 1) HCPs expressed positive attitudes towards doxy-PEP; 2) antimicrobial resistance concerns limit enthusiasm for some HCPs; 3) additional data about the long-term safety of doxy-PEP would improve their confidence; and 4) development of guidelines would facilitate the prescription of doxy-PEP, including eligibility, dosing instructions, and treatment management., Conclusion: HCPs were motivated to prescribe doxy-PEP with almost 20% already having prescribed it. Guidelines and data about long-term safety, especially antimicrobial resistance, would facilitate introduction of doxy-PEP into clinical practice., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

Doxycycline post-exposure prophylaxis (doxy-PEP) reduces the risk of bacterial sexually transmitted infections (STIs) among men who have sex with men and transgender women. In the United States, doxy-PEP is in an early stage of integration into clinical practice, and national guidelines for its use were recently released. The goal of this manuscript is to provide practical guidance for clinicians who are considering or currently prescribing doxy-PEP. We address five clinical questions using post hoc analyses of data from the DoxyPEP randomized controlled trial and discuss the potential implications and limitations of each question with the goal of informing clinical practice and implementation of doxy-PEP programs. The questions address patient eligibility criteria for doxy-PEP, the expected benefit and associated doxy-PEP doses for the average patient, the initial number of doses prescribed, and laboratory monitoring of persons taking doxy-PEP., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for tuberculosis prevention in people with human immunodeficiency virus (HIV). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. AIDS Clinical Trials Group A5372 evaluated the effect of 1HP on the pharmacokinetics of twice-daily dolutegravir., Methods: A5372 was a multicenter, pharmacokinetic study in people with HIV (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA <50 copies/mL. Participants received daily rifapentine/isoniazid (600 mg/300 mg) for 28 days as part of 1HP. Dolutegravir was increased to 50 mg twice daily during 1HP, and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment., Results: Thirty-two participants (41% female; 66% Black/African; median [Q1, Q3] age, 42 [34, 49] years) were included in the pharmacokinetic analysis; 31 had HIV RNA <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 versus 1987 ng/mL (1331, 2278) on day 28 (day 28:day 0 geometric mean ratio, 1.05 [90% confidence interval, .93-1.2]; P = .43). No serious adverse events were reported., Conclusions: Dolutegravir trough concentrations with 50 mg twice-daily dosing during 1HP treatment were greater than those with standard-dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice-daily dolutegravir use in combination with 1HP for tuberculosis prevention., Clinical Trials Registration: NCT04272242., Competing Interests: Potential conflicts of interest. A.F.L. has contracts for clinical research unrelated to this work from Gilead, ViiV, and Merck; consulting fees from ViiV. A.A. reports grants from Gilead, ViiV, Roche, GSK and MSD unrelated to this work. S.S. reports grants from ViiV unrelated to the present work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Doxycycline post-exposure prophylaxis (doxy-PEP) reduces bacterial sexually transmitted infections among men who have sex with men and transgender women. Although poised for widespread clinical implementation, the impact of doxy-PEP on antimicrobial resistance remains a primary concern as its effects on the gut microbiome and resistome, or the antimicrobial resistance genes (ARGs) present in the gut microbiome, are unknown. To investigate these effects, we studied participants from the DoxyPEP trial, a randomized clinical trial comparing doxy-PEP use, a one-time doxycycline 200-mg dose taken after condomless sex (DP arm, n = 100), to standard of care (SOC arm, n = 50) among men who have sex with men and transgender women. From self-collected rectal swabs at enrollment (day-0) and after 6 months (month-6), we performed metagenomic DNA sequencing (DNA-seq) or metatranscriptomic RNA sequencing (RNA-seq). DNA-seq data were analyzable from 127 samples derived from 89 participants, and RNA-seq data were analyzable from 86 samples derived from 70 participants. We compared the bacterial microbiome and resistome between the two study arms and over time. The median number of doxycycline doses taken since enrollment by participants with DNA-seq data was zero (interquartile range (IQR): 0-7 doses) for the SOC arm and 42 (IQR: 27-64 doses) for the DP arm. Tetracycline ARGs were detected in all day-0 DNA-seq samples and in 85% of day-0 RNA-seq samples. The proportional mass of tetracycline ARGs in the resistome increased between day-0 and month-6 in DP participants from 46% to 51% in the metagenome (P = 2.3 × 10 -2 ) and from 4% to 15% in the metatranscriptome (P = 4.5 × 10 -6 ), but no statistically significant increases in other ARG classes were observed. Exposure to a higher number of doxycycline doses correlated with proportional enrichment of tetracycline ARGs in the metagenome (Spearman's ρ = 0.23, P = 9.0 × 10 -3 ) and metatranscriptome (Spearman's ρ = 0.55, P = 3.7 × 10 -8 ). Bacterial microbiome alpha diversity, beta diversity and total bacterial mass did not differ between day-0 and month-6 samples from DP participants when assessed by either DNA-seq or RNA-seq. In an abundance-based correlation analysis, we observed an increase over time in the strength of the correlation between tetracycline ARGs and specific bacterial taxa, including some common human pathogens. In sum, doxy-PEP use over a 6-month period was associated with an increase in the proportion of tetracycline ARGs comprising the gut resistome and an increase in the expression of tetracycline ARGs. At 6 months of doxy-PEP use, no residual differences were observed in alpha and beta diversity or taxonomic composition of the gut microbiome. As doxy-PEP is implemented as a public health strategy, further studies and population-level surveillance of doxycycline-resistant pathogens are needed to understand the implications of these findings. ClinicalTrials.gov registration number: NCT03980223 ., (© 2024. The Author(s).)

For COVAIL recipients of a COVID-19 Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Hepatitis C virus (HCV) reinfection after curative treatment remains a concern for people who inject drugs., Objective: To assess the incidence of HCV reinfection and associated risk factors., Design, Setting, and Participants: This cohort study is a secondary analysis of a randomized clinical trial that was conducted across opioid treatment programs and community health centers in the US between September 2016 and August 2018. The current analyses were performed in March 2022. People who inject drugs who achieved sustained virologic response (SVR) were followed for up to 42 months., Exposure: Patients were randomly assigned to receive modified directly observed therapy or patient navigation., Main Outcomes and Measures: The primary outcome was rate of HCV reinfection. Change in reinfection rates over time was assessed using a Poisson regression model., Results: A total of 415 participants (mean [SD] age, 44.7 [11.5] years; 302 male [72.8%]) achieved a SVR and had 1 or more post-SVR assessments for HCV RNA. Overall, 302 (72.8%) reported recent injection drug use, 192 (46.3%) were living in unstable housing, and 313 (75.4%) had received recent methadone or buprenorphine for opioid use disorder. The overall reinfection rate was 11.4 per 100 person-years at risk (95% CI, 8.7-14.7 per 100 person-years at risk) over 518 person-years of follow-up. Reinfection rates varied significantly across sites, ranging from 2.9 per 100 person-years at risk (95% CI, 0.1-16.3 per 100 person-years) to 25.2 per 100 person-years at risk (95% CI, 15.6-38.5 per 100 person-years at risk) (P = .006). There was a significant decrease in incident reinfection with increasing post-SVR follow-up (weeks 0-24, 15.5 per 100 person-years; 95% CI, 10.3-22.3 per 100 person-years; weeks 73-144, 4.3 per 100 person-years; 95% CI, 0.9-12.5 per 100 person-years; P = .008). Reinfection rates were lower for participants aged 40 years or older than for younger participants (adjusted incidence rate ratio, 0.32; 95% CI, 0.18-0.57) and for participants for whom methamphetamine was not detected in urinary drug screening compared with participants for whom methamphetamine was detected (adjusted incidence rate ratio, 0.41; 95% CI, 0.21-0.82). Participants who reported injection drug use within the preceding 3 months had higher risk of reinfection than those who did not have recent injection drug use (adjusted incidence rate ratio, 3.33; 95% CI, 1.86-5.97)., Conclusions and Relevance: In this cohort study of people who injected drugs and were treated for HCV infection in community settings, reinfection was high in the period immediately after SVR but decreased significantly over time. These findings highlight the importance of early intervention to prevent reinfection., Trial Registration: ClinicalTrials.gov Identifier: NCT02824640.

Doxycycline postexposure prophylaxis (doxy-PEP) reduces sexually transmitted infections (STIs) in men who have sex with men (MSM) and transgender women (TGW). In a clinical trial of doxy-PEP, we sought to assess acceptability, impact, and meaning of doxy-PEP use among MSM/TGW. We conducted semistructured, in-depth 1:1 interviews with MSM and TGW enrolled in the intervention arm of the Doxy-PEP study. We queried motivations for and meaning of use, attitudes, beliefs, adherence, effect on sexual behaviors, and partner, community, and structural factors related to use. We coded interview transcripts into content areas, followed by thematic analysis. We interviewed 44 participants (median age 38), 2% were TGW, 17% Black, 61% White, 30% Hispanic, and 45% persons with HIV. We identified three overarching themes. First, participants found doxy-PEP acceptable, and believed it was effective based on their history of STIs, easy to adhere to, and acceptable to sex partners. Second, doxy-PEP benefited their quality of life and mental health, offering "peace of mind" by reducing their anxiety about acquisition or unwitting transmission of STIs. Participants reported feeling more "in control" of preventing STIs, and positive about supporting their personal, partner, and community health. Third, impact on sexual behavior was variable, with most reporting no change or a brief initial change. Participants in a multi-site clinical trial of doxycycline for STI prevention perceived it to be efficacious, and that it provided quality-of-life benefits, including reduced anxiety and sense of control over sexual health. Doxy-PEP had limited impact on sexual behavior. Clinicaltrials.gov: NCT03980223.

Competing Interests: Conflict of Interest and Sources of Funding: J.S. is a member of Merck KGaA's Ethics Advisory Panel and Stem Cell Research Oversight Committee, a member of IQVIA's Ethics Advisory Panel, and a member of Aspen Neurosciences' Clinical Advisory Panel He was previously a member of a Merck Data Monitoring Committee and a consultant to Biogen. None of these activities are related to the material discussed in this manuscript. Fenway Health is a subrecipient of a grant to Mpact: Global Action for Gay Men's Health and Rights from Glaxo Smith Kline for a research project on knowledge of and attitudes toward hepatitis A and B vaccination among gay and bisexual men and transgender people in the United States and Mexico. S.C. is the principal investigator of this project. S.C. is on the Patient Advocate Steering Committee for Prostate Cancer Clinical Trials for Janssen Global Services representing gay and bisexual men and transgender women. None of these activities are related to the material discussed in this article. C.C. has served as an advisory board member to Gilead Sciences, Merck, and Viiv and an expert witness for Gilead Sciences. None of these activities are related to the material discussed in this article. Stephanie E. Cohen has received laboratory support from Cepheid and Hologic and medication donation from Mayne Pharma, to support the conduct of the DoxyPEP study. A.F.L. has received laboratory support from Cepheid and Hologic and medication donation from Mayne Pharma, to support the conduct of the DoxyPEP study. She has received grant support from Gilead, Merck, and Viiv to UCSF, unrelated to this work. Fenway Health is the recipient of funding from the Centers for Disease Control and Prevention through a subcontract with National Association of County and City Health Officials to assess the roll-out of DoxyPEP. K.H.M. is the subcontract principal investigator. Fenway Health has also received unrestricted research grants from Gilead Sciences and Merck, Inc., and K.H.M. is the principal investigator for those grants. K.H.M. is on scientific advisory boards for Gilead Sciences and Merck, Inc., focusing on HIV prevention. H.A.T.'s effort is funded by the National Institutes of Health Clinical Center, Department of Bioethics.

Over the past two decades, cases of sexually transmitted infections (STIs) due to syphilis, gonorrhea, and chlamydia have been rising in the United States, disproportionately among gay, bisexual, and other men who have sex with men (MSM), as well as racial and ethnic minorities of all genders. In this review, we address updates about the evidence on doxycycline post-exposure prophylaxis (doxy-PEP) for prevention of bacterial STIs, including efficacy, safety, antimicrobial resistance (AMR), acceptability, modeling population impact, and evolving guidelines for use. Equitable implementation of doxy-PEP will require evaluation of who is offered and initiates it, understanding patterns of use and longer-term STI incidence and AMR, provider training, and tailored community education., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost., Competing Interests: Potential conflicts of interest. A. R. B. has received research support from NIH-NIAID, grants from Pfizer, Cyanvac, Moderna, Vaccine.co and Merck as well as consulting fees from Janssen and GSK. She serves as DSMB member for NIH, IDSA Public Health Committee. Honoraria as a speaker from Virology Education. L. R. B. has received grants from Wellcome Trust, Gates Foundation, NIH/Harvard Medical School through institution. Serves as member of DSMB for NIH and AMDAC for FDA. Dr Baden is involved in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), Covid Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. D. J. D. has received a contract from Leidos Biomedical/NIH research to conduct the clinical trial through institution. A. R. F. has received grants from Janssen, Pfizer, Merck, BioFire Diagnostics, Moderna, Vaccine company and CyanVac through institution. Consultant fees from Arrow Pharmaceutical, ADMA biologics, GSK, and honoraria as a speaker from Sanofi and GlaxoSmithKline. Serves as DSMB advisory boards for Novavax and received travel/meeting support from GlaxoSmithKline. S. E. F. has received funding from Leidos to Saint Louis University to conduct Protocol DMID 22-0004. Funding was also received to conduct the Moderna and Janssen trials phase 3 SARS-CoV-2 trials. Serves as DSMB for HVTN Safety Monitoring Board. D. N. F. has as a contract from CDC and is the site PI for DN Fusco study of COVID in Special Populations. D. N. F. served on an HBV Advisory board for Gilead related to hepatitis C & B viruses and Axcella related to Long COVID. P. A. G. has received funding from NIH. PAG has a patent for COVID-19 monoclonal not developed clinically and received consulting fees from International AIDS Society as speaker. L. C. I. has received support from NIH, Moderna, Pfizer, and Sanofi. L. C. I. has also received grants from GSK, Merck, Sharpe & Dohme Corp, CDC, Novavax, Pediatric Emergency Medicine Associates, and NIH/NLM/National Institute on Minority Health and Health Disparities as well as consulting fees from Moderna. L. C. I. has received honoraria as a speaker from American Academy of Pediatrics, Rockefeller University, Moderna, CDC and American Academy of Pediatrics- Georgia Chapter. L. C. I. Serves on Data Safety Monitoring for NIH-Phase 2 Vaccine Trial for Monkeypox, Moderna Scientific Advisory Board- North America, and CoVID-19 Task Force, Georgia. L. C. I. has a leadership role Break the Cycle of Health Disparities Inc, the Center for Spatial Analytics of the Georgia Institute of Technology, and the American Academy of Pediatrics (Executive Board for Section on Infectious Diseases). L. C. I. has received travel/meeting support from the American Academy of Pediatrics and Moderna. L. A. J. has received funding from NIH for support for this study, funding from Pfizer to support a clinical trial and contract funding for research support from the CDC and the NIH, all through institution. L. A. J. also reports unpaid participation on Data Safety Monitoring Boards for NIH funded clinical trials. S. K. has received research grants from NIH, Pfizer, U.S. Centers for Disease Control and Prevention, Meisa, Emergent BioSolutions. S. K. also received support from American Academy of Pediatrics as speaker. A. C. K. has received research support from COVID-19 Adaptive Variance Immunologic Landscape Trial # 28C15000NYUPG266894. S. J. L. has received NIH grants through institution. Consulting fees from Hookipa Pharma. A. F. L. has received grants from Merck, Gilead and, GSK through institution as well as consulting fees from Vir Biotechnology. A. F. L. has also received travel support from Merck to attend a required investigator meeting, testing kits and supplies to support research study from Hologic, Cepheid and medication donated by Mayne Pharma to support research study. M. M. has received funding from Emmes through NIH contract # HHSN272201500002C. L. J. M. has received funding from Emmes through NIH contract # HHSN272201500002C. D. C. M. has received funding from NIH/75N93019C00050-21A: CIVICS A- Option 21A-DMID Trials of COVID-19 Vaccines. J. M. has received funding from Division of Microbiology and Infectious Diseases, contract # 75N93021C00012. A. N. has received support from NIH-NIAID, CEIRR (Centers of Excellence for Influenza Research and Response) and Gates Cambridge Trust as well as grants from NIH-NIAID R01. R. M. N. has received grants from NIAID-DMID and travel/meeting support from Moderna. C. M. P. has received funding from NIAID UM1AI148684. R. M. P. has received funding from NIH DMID COVAIL as well as grants from Janssen, Moderna and NIH through institution. N. G. R. has received research grants from NIH, Pfizer, Merck, Sanofi, Quidel, Immorna, Vaccine Company and Lilly through her institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi and Moderna. N. G. R. serves as DSMB on safety committees for ICON, Micron and EMMES and is a member of the Moderna, Sanofi, Seqirus and Pfizer selected Advisory boards. Plays leadership advisory role for ARLG, TMRC, CDC-Pertussis challenge, Clinical Infectious Diseases. Equipment supports from Georgia Research Alliance. D. J. S. has received support from NIH-NIAID CEIRR, grants from NIH-NIAID R01, and travel support from NIH-NIAID CEIRR for NIH-related meetings. K. T. has received funding from Emmes through NIH contract # HHSN272201500002C. E. B. W. has received funding from Leidos Biomedical Research AGREEMENT NO. 22CTA-DM0009 as well as grants from Pfizer, Moderna, Sequiris, Clinetic, and Najit Technologies, with payments made to institution. E. B. W. has also received honoraria as a speaker from College of Diplomates of the American Board of Pediatric Dentistry, consulting fees from Iliad Biotechnologies, and travel/meeting support from the American Academy of Pediatrics. E. B. W. serves as member of Vaxcyte Scientific Advisory board. P. L. W. has received subcontract funding from NIH for this study as well as NIH grant funding and contract funding from Pfizer through University of Iowa. P. L. W. has also received consulting fees from Pfizer and serves on DSMB advisory board for Emmes Corporation, Blue Lake. M. B. has received research grants from Leidos Biomedical Research and Pfizer through institution. J. A. W. has received funding from NIH-DMID 75N91019D00024. R. L. A., T. M. B., S. M. M., M. K. M., J. H. B., S. C., C. L., P. C. R., R. R. authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants., Methods: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis., Results: Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/μl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence., Conclusion: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 ., (© 2023. The Author(s).)

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines., Competing Interests: Potential conflicts of interest. E. J. A. has received grants from Pfizer, Moderna, Janssen, GSK, Sanofi, Micron, and Regeneron through institution as well as consulting fees from Pfizer, Janssen, Moderna, and Sanofi. E. J. A. serves on safety/advisory boards for Sanofi, ACI Clinical/WCG and Kentucky Bioscience, Inc. A. R. B. has received research support from NIH-NIAID, grants from Pfizer, Cyanvac, and Merck as well as consulting fees from Janssen and GSK. L. R. B. has received grants from Wellcome Trust, Gates Foundation, NIH/Harvard Medical School through institution. Serves as member of DSMB for NIH and AMDAC for Food and Drug Administration (FDA). L. R. B. is involved in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. D. J. D. has received a contract from Leidos Biomedical research to conduct the clinical trial through institution. A. R. F. has received grants from Janssen, Pfizer, Merck, BioFire Diagnostics, and CyanVac through institution, consultant fees from Arrowhead and Icosavax, and honoraria as a speaker from Moderna and GlaxoSmithKline. A. R. F. also serves on safety/advisory boards for Novavax and received travel/meeting support from GlaxoSmithKline. S. E. F. has received funding from Leidos to Saint Louis University to conduct Protocol DMID22-0004. D. N. F. has as a contract from Centers for Disease Control and Prevention (CDC) and is the site principal investigator (PI) for clinical trials from Gilead, Regeneron, and MetroBiotech, LLC. She is the PI on 1 investigator-initiated award from Gilead and the co-PI on another investigator-initiated award from Gilead. D. N. F. served on an HBV Advisory board for Gilead in 2021 and received payment for expert testimony not related to COVID in 2022. P. A. G. has received funding for COVAIL clinical trial. P. A. G. has also received consulting fees from Janssen Vaccines. L. C. I. has received support for the present manuscript from NIH-NIAID/DMID, Moderna, Pfizer, and Sanofi. L. C. I. has also received grants from GSK, Merck, Sharpe & Dohme Corp, CDC, Novavax, AHRQ, and NIH/NLM/NIMHD as well as consulting fees from Moderna, CDC, and Pediatric Emergency Medicine Associates, LLC. L. C. I. has received honoraria as a speaker from American Academy of Pediatrics, Rockefeller University, and American Academy of Pediatrics- Georgia Chapter. L. C. I. serves on Data Safety Monitoring for NIH-Phase 2 Vaccine Trial for Monkeypox, Moderna Scientific Advisory Board- North America, and COVID-19 Task Force, Georgia. L. C. I. has a leadership role in the Pediatric Infectious Disease Society, serves as board member on the Emory University- Pediatric and Reproductive Environmental Health Scholars-Southeastern, the Center for Spatial Analytics of the Georgia Institute of Technology, and the American Academy of Pediatrics (Executive Board for Section on Infectious Diseases). L. C. I. has received travel/meeting support from the American Academy of Pediatrics and Moderna. L. A. J. has received funding from NIH for support for this study, funding from Pfizer to support a clinical trial and contract funding for research support from the CDC and the NIH, all through institution. L. A. J. also reports unpaid participation on Data Safety Monitoring Boards for NIH funded clinical trials. S. J. L. has received NIH grants through institution. A. F. L. has received grants from Merck, Gilead, and ViiV through institution as well as consulting fees from Vir Biotechnology. A. F. L. has also received travel support from Merck to attend a required investigator meeting, testing kits and supplies to support research study from Hologic, and medication donated by Mayne Pharma to support research study. M. M. has received funding from Division of Microbiology and Infectious Diseases for contract number 75N93021C00012. D. C. M. has received funding from NIH/75N93019C00050-21A: CIVICS A- Option 21A-DMID Trials of COVID-19 Vaccines. J. M. has received funding from Division of Microbiology and Infectious Diseases, contract number 75N93021C00012. A. N. has received support from NIH-NIAID, CEIRR (Centers of Excellence for Influenza Research and Response) and Gates Cambridge Trust as well as grants from NIH-NIAID R01. R. M. N. has received grants from Moderna and Janssen and travel/meeting support from Moderna. C. M. P. has received funding from NIAID UM1AI148684. R. M. P. has received funding from NIH DMID COVAIL as well as grants from Janssen, Moderna, and NIH through institution. N. G. R. has received research grants from Pfizer, Merck, Sanofi, Quidel, and Lilly through institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi. N. G. R. serves on safety committees for ICON and EMMES and is a member of the Moderna Advisory board. D. J. S. has received support from NIH-NIAID CEIRR, grants from NIH-NIAID R01, and travel support from NIH-NIAID CEIRR for NIH-related meetings. K. T. has received funding from Division of Microbiology and Infectious Diseases contract number 75N93021C00012. E. B. W. has received funding from Leidos Biomedical Research agreement number. 22CTA-DM0009 as well as grants from Pfizer, Moderna, Sequiris, Clinetic, and Najit Technologies, with payments made to institution. E. B. W. has also received honoraria as a speaker from College of Diplomates of the American Board of Pediatric Dentistry, consulting fees from Iliad Biotechnologies, and travel/meeting support from the American Academy of Pediatrics. E. B. W. serves as member of Vaxcyte Scientific Advisory board. P. L. W. has received subcontract funding from NIH for this study as well as NIH grant funding and contract funding from Pfizer through University of Iowa. P. L. W. has also received consulting fees from Pfizer and serves on safety/advisory board for Emmes Corporation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In people with chronic hepatitis C virus (HCV) infection, viral eradication is associated with improved health-related quality of life (HRQOL)., Objective: To assess changes in HRQOL among participants receiving opioid agonist therapy undergoing treatment for HCV infection., Methods: COSTAR (NCT02251990) was a randomized, double-blind, placebo-controlled study. Adults with HCV infection on opioid agonist therapy received elbasvir (50 mg)/grazoprevir (100 mg) or placebo for 12 weeks. HRQOL was evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF-36v2) Acute Form. Participants remained blinded until 4 weeks after end of treatment., Results: Overall, 201 participants received elbasvir/grazoprevir and 100 participants received placebo. Treatment difference mean change from baseline scores (elbasvir/grazoprevir minus placebo) indicated an improvement in HRQOL at 4 weeks after end of treatment in participants receiving elbasvir/grazoprevir versus those receiving placebo, driven by declining HRQOL in those receiving placebo and improved HRQOL in certain domains among participants receiving elbasvir/grazoprevir. Notable differences in SF-36v2 scores were evident in the general health (mean treatment difference [MTD], 6.00; 95% CI, 1.37-10.63), vitality (MTD, 6.81; 95% CI, 1.88-11.75), and mental health (MTD, 5.17; 95% CI, 0.52-9.82) domains and in the mental component summary score (mean, 2.83; 95% CI, 0.29-5.37). No notable between-treatment differences were evident at treatment weeks 4 or 12., Conclusion: HRQOL in patients receiving medication for opioid dependence was improved following treatment for HCV infection with elbasvir/grazoprevir, suggesting that eradication of HCV infection with direct-acting antivirals is associated with improved HRQOL., Trial Registration Number: ClinicalTrials.gov, NCT02251990.

Background: Interventions to reduce sexually transmitted infections (STIs) among men who have sex with men (MSM) are needed., Methods: We conducted an open-label, randomized study involving MSM and transgender women who were taking preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection (PrEP cohort) or living with HIV infection (persons living with HIV infection [PLWH] cohort) and who had had Neisseria gonorrhoeae (gonorrhea), Chlamydia trachomatis (chlamydia), or syphilis in the past year. Participants were randomly assigned in a 2:1 ratio to take 200 mg of doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis) or receive standard care without doxycycline. STI testing was performed quarterly. The primary end point was the incidence of at least one STI per follow-up quarter., Results: Of 501 participants (327 in the PrEP cohort and 174 in the PLWH cohort), 67% were White, 7% Black, 11% Asian or Pacific Islander, and 30% Hispanic or Latino. In the PrEP cohort, an STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group and 82 of 257 quarterly visits (31.9%) in the standard-care group, for an absolute difference of -21.2 percentage points and a relative risk of 0.34 (95% confidence interval [CI], 0.24 to 0.46; P<0.001). In the PLWH cohort, an STI was diagnosed in 36 of 305 quarterly visits (11.8%) in the doxycycline group and 39 of 128 quarterly visits (30.5%) in the standard-care group, for an absolute difference of -18.7 percentage points and a relative risk of 0.38 (95% CI, 0.24 to 0.60; P<0.001). The incidences of the three evaluated STIs were lower with doxycycline than with standard care; in the PrEP cohort, the relative risks were 0.45 (95% CI, 0.32 to 0.65) for gonorrhea, 0.12 (95% CI, 0.05 to 0.25) for chlamydia, and 0.13 (95% CI, 0.03 to 0.59) for syphilis, and in the PLWH cohort, the relative risks were 0.43 (95% CI, 0.26 to 0.71), 0.26 (95% CI, 0.12 to 0.57), and 0.23 (95% CI, 0.04 to 1.29), respectively. Five grade 3 adverse events and no serious adverse events were attributed to doxycycline. Of the participants with gonorrhea culture available, tetracycline-resistant gonorrhea occurred in 5 of 13 in the doxycycline groups and 2 of 16 in the standard-care groups., Conclusions: The combined incidence of gonorrhea, chlamydia, and syphilis was lower by two thirds with doxycycline postexposure prophylaxis than with standard care, a finding that supports its use among MSM with recent bacterial STIs. (Funded by the National Institutes of Health; DoxyPEP ClinicalTrials.gov number, NCT03980223.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals., Methods: To explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746)., Results: We observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints., Conclusion: Robust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic., Competing Interests: JM, BA, AAA, TE, KS, AMS, MP, PAS, DW, TV, JAG, and EJK are current employees of AstraZeneca and hold or may hold AstraZeneca stock. HB and NP are contractors to AstraZeneca via Bogier consulting. BJ is a contractor to AstraZeneca via Cytel. SS is a contractor to AstraZeneca via Joule/System One. ARF has received institutional grants for research from Pfizer, Merck, Sharpe and Dohme, Janssen, and BioFire Diagnostics and has received fees for serving on Novavax COVID-19 vaccine Data and Safety Monitoring Board. MES declares grants from the NIH and NIAID during the conduct of the study and institutional research grants from the Bill and Melinda Gates Foundation, Gilead Sciences, Janssen Global Services, LLC, Merck, and Sanofi Pasteur Inc. AFL has received institutional research grants from AstraZeneca and Gilead Sciences. GCP has received institutional research grants from AstraZeneca, Pfizer, and Moderna. SAR has received institutional grants from the NIH and NIAID from clinical trial enrolment and provides pro bono consultancy to Novimmune for novimab. MLR declares funding for consultancy from the Walter Reed Army Institute of Research and for serving on their behalf in Operation Warp Speed. C-PR has received institutional research grants from Gilead Sciences and ViiV Healthcare, honoraria for lectures from Gilead Sciences, ViiV Healthcare and Vindico CME, and sits on advisory boards for Janssen, Gilead Sciences, and ViiV Healthcare. BES has received research funding from the US government under the COVID-19 Prevention Network initiative, institutional research grants from Gilead Sciences, ViiV Healthcare, and the University of Chicago and payment or honoraria from MATEC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from AstraZeneca. The funder had the following involvement with the study with input from the external authors: study design; collection, analysis and interpretation of data; the writing of this article and the decision to submit it for publication. The first draft of the manuscript was written under the direction of the authors by a medical writer funded by AstraZeneca., (Copyright © 2023 Maaske, Sproule, Falsey, Sobieszczyk, Luetkemeyer, Paulsen, Riddler, Robb, Rolle, Sha, Tong, Ahani, Aksyuk, Bansal, Egan, Jepson, Padilla, Patel, Shoemaker, Stanley, Swanson, Wilkins, Villafana, Green and Kelly.)

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., Competing Interests: Declaration of interests OF-N has served on advisory panels for Gilead Sciences and reports research funds from AbbVie paid to Johns Hopkins University. JF has received research grant support from Gilead Sciences. AYK has served on advisory boards for Biomarin. AFL received research grant support from Gilead and Merck. The Task Force for Global Health receives funds for the general support of the Coalition for Global Hepatitis Elimination from Abbott, Gilead, AbbVie, Merck, Siemens, Roche, Pharco, Zydus-Cadila, governmental agencies, and philanthropic organisations. AHL has served on advisory boards for Gilead Sciences and Merck Pharmaceuticals and received research funding from Gilead Sciences. SHM has received speaker fees from Gilead Sciences. LET has received UpToDate Royalties for peer review of viral hepatitis topics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs., Objective: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT)., Design: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688)., Setting: 55 clinical trial sites in 13 countries., Patients: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT., Intervention: No treatments were administered., Measurements: Serum samples were assessed for HCV reinfection. Urine drug screening was performed., Results: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up., Limitations: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown., Conclusion: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle-syringe sharing., Primary Funding Source: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Until the COVID-19 pandemic, San Francisco's hepatitis C virus (HCV) elimination initiative, End Hep C SF, was expanding and refining HCV testing and treatment strategies citywide, making progress toward local HCV elimination goals. Although a shelter-in-place health order issued in March 2020 categorized HCV testing as an "essential service," most HCV testing and treatment immediately stopped until COVID-19-safe protocols could be implemented. During the 14 months of pandemic-related organizational closures, End Hep C SF transitioned to a 100% virtual model, maintaining regularly scheduled meetings. Community-based HCV antibody testing decreased 80% from February to April 2020, and HCV treatment initiation also decreased, although both services started to rebound in mid-to-late 2020, partially as a result of End Hep C SF collaborations. End Hep C SF service providers, clinicians, and advocates reported that the continuous communication and common agenda of End Hep C SF-2 principles of the collective impact initiative-served as a familiar touchpoint and helpful source of information during this isolating and uncertain time. Ultimately, End Hep C SF allowed us to continue HCV elimination strategies through 6 lessons learned: maintaining HCV treatment access through telehealth and mobile services; leveraging research studies that provided HCV testing and treatment; offering HCV screening and linkage to care in tandem with COVID-19-related initiatives; being flexible and inventive, such as administering HCV treatment to residents of shelter-in-place hotels; establishing a data dashboard to track HCV testing and treatment; and relying on partnerships to solve problems and avoid burnout.

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact., Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics., Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants)., Exposure: Receipt of CCP., Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI., Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs., Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19., Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475., Findings: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group., Interpretation: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo., Funding: The National Institute of Allergy and Infectious Diseases (USA)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment., Methods: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis)., Results: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred., Discussion: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

We characterized the antibody composition of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) and the immunologic responses of hospitalized COVID-19 patients after receiving CCP or nonimmune fresh frozen plasma. Despite selection of CCP with significantly higher total immunoglobulin G than recipients, neutralizing antibody levels did not differ between donor plasma and CCP recipients., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance., Methods: In this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%., Results: Five hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, -0.7% [95.001% confidence interval {CI}, -2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF., Conclusions: The single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs., Clinical Trials Registration: NCT03110380., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

At the 2021 Conference on Retroviruses and Opportunistic Infections, there was a focus on progress toward hepatitis C virus (HCV) microelimination in geographic regions and targeted populations. HCV elimination is facilitated by well-tolerated, highly effective HCV treatment that requires essentially no on-treatment monitoring in most patients, as highlighted by the MINMON (Minimal Monitoring Study or A5360) study, and that should be increasingly available to children with new data supporting feasible treatment in younger patients. Challenges to HCV elimination include HCV reinfection via sexual exposure in men who have sex with men (MSM) and continued barriers to diagnosis and access to HCV treatment. Hepatitis B virus (HBV) suppression may take years in HIV/HBV-coinfected patients. This may have important consequences as the risk for hepatocellular carcinoma was associated in a dose-dependent manner with HBV viral load and was lowest in those with sustained undetectable HBV, highlighting the need for HBV DNA monitoring during therapy. Public health programs should prioritize improving hepatitis A and hepatitis B vaccination in at-risk populations, including people with HIV, as vaccinations rates for these preventable diseases continue to be suboptimal in many settings. Fatty liver disease, heavy alcohol use, antiretroviral therapy, and COVID-19 infection were also examined as drivers of hepatic disease in HIV infection.

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known., Methods: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15., Results: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003)., Conclusions: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.)., (Copyright © 2020 Massachusetts Medical Society.)

Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were (i) longitudinal clinical, pharmacokinetic (PK), and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n = 116), (ii) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, (iii) a population PK model of HCQ, and (iv) a model relating chloroquine PKs to corrected QT (QTc) prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ PKs (P < 0.001). The extrapolated patient half-maximal effective concentration (EC 50 ) was 4.7 µM, comparable to the reported in vitro EC 50s . HCQ doses > 400 mg b.i.d. for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared with lower dose (≤ 400 mg daily) regimens. However, HCQ doses > 600 mg b.i.d. were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Bacterial sexually transmitted infections (STIs) have been increasing over the past 2 decades in gay, bisexual, and other men who have sex with men. With the widespread use of early human immunodeficiency virus (HIV) treatment, which virtually eliminates transmission risk, and the availability of HIV pre-exposure prophylaxis, there have been attitudinal changes regarding HIV infection with resultant increases in sexual contact and declines in condom use. Doxycycline is used for primary prophylaxis in a number of infectious diseases. We conducted a state-of-the-art review to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis and other STIs. International academic and government experts met in March 2019 to frame the initial inquiry, which was supplemented by focused literature searches. Two small short-term randomized controlled trials examining doxycycline prophylaxis found high efficacy. Five additional clinical studies are underway or in development. Studies differed in design, population, outcomes, and safety measures. Doxycycline prophylaxis for bacterial STIs shows promise. Better and more robust data are needed on efficacy; target population; community acceptability; behavioral risk compensation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness; and risk-benefit., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Well-tolerated, highly effective HCV treatment, known as direct-acting antivirals (DAAs), is now recommended for all people living with HCV, providing the tools for HCV elimination. We sought to understand treatment barriers among low-income HIV/HCV coinfected patients and providers with the goal of increasing uptake., Methods: In 2014, we conducted 26 interviews with HIV/HCV co-infected patients and providers from a San Francisco clinic serving underinsured and publically-insured persons to explore barriers impacting treatment engagement and completion. Interview transcripts were coded, and a thematic analysis was conducted to identify emerging patterns., Results: Conditions of poverty-specifically, meeting basic needs for food, shelter, and safety-undermined patient perceptions of self-efficacy to successfully complete HCV treatment programs. While patient participants expressed interest in HCV treatment, the perceived burden of taking daily medications without strong social support was an added challenge. This need for support contradicted provider assumptions that, due to the shorter-course regimens, support is unnecessary in the DAA era., Conclusions: Interferon-free treatments alone are not sufficient to overcome social-structural barriers to HCV treatment and care among low-income HIV/HCV co-infected patients. Support for patients with unmet social needs may facilitate treatment initiation and completion, particularly among those in challenging socioeconomic situations., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

HIV/HCV coinfected patients are a priority for direct acting antiretroviral (DAA) treatment, yet barriers to treating vulnerable patients persist. This study surveyed safety net clinic patients and providers to quantify their preferences for DAA treatment and prioritize modifiable barriers. Preferences were assessed using best-worst scaling. General linear mixed models were used to determine whether attributes differed in importance and whether patients and providers valued attributes differently. 158 HIV/HCV coinfected patients and 49 providers participated. Patients and providers had strong preferences for treatment within the medical homes where patients receive HIV care. Support such as reminders and advice numbers were also important, but were more important to providers than patients. Providers identified lack of insurance coverage for DAA as the most significant barrier. Providers rated HIV primary care providers as best suited to deliver DAA to HIV+ patients. Addressing structural barriers is essential for increasing DAA treatment in safety net settings.

At the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), there was a major focus on hepatitis C virus (HCV) elimination and improving each component of the hepatitis C care cascade. Many interventions showed promising improvements in diagnosis and linkage to care. Settings with robust access to direct-acting antivirals (DAAs) continue to demonstrate the role of HCV treatment as prevention. However, substantial barriers to accessing curative therapy remain. Reinfection after treatment presents an important barrier to elimination, particularly in some populations of men who have sex with men (MSM). MSM without HIV infection are at an elevated risk for sexual acquisition of HCV, and several studies reported HCV rates that were as high as those seen in MSM living with HIV. There was also a focus on HCV and HBV in pregnant women. Rates of HCV infection in women of child-bearing potential have increased, making prenatal diagnosis a priority. In the first study of HCV treatment during pregnancy, sofosbuvir/ledipasvir started at 28 weeks of gestation led to cure in 8 pregnant women. Hepatitis B virus (HBV)-active antiretrovirals are generally effective in suppressing HBV but have low rates of surface antigen loss despite long term treatment. Initial results from novel laboratory assessments of intrahepatic HBV viral infection events were presented, hopefully paving the way for more effective HBV treatment strategies to control and potentially cure HBV.

Importance: New guidelines recommend that molecular testing replace sputum-smear microscopy to guide discontinuation of respiratory isolation in patients undergoing evaluation for active tuberculosis (TB) in health care settings., Objective: To evaluate the implementation and impact of a molecular testing strategy to guide discontinuation of isolation., Design, Setting, and Participants: Prospective cohort study with a pragmatic, before-and-after-implementation design of 621 consecutive patients hospitalized at Zuckerberg San Francisco General Hospital and Trauma Center who were undergoing sputum examination for evaluation for active pulmonary TB from January 2014 to January 2016., Interventions: Implementation of a sputum molecular testing algorithm using GeneXpert MTB/RIF (Xpert; Cepheid) to guide discontinuation of isolation., Main Outcomes and Measures: We measured the proportion of patients with molecular testing ordered and completed; the accuracy of the molecular testing algorithm in reference to mycobacterial culture; the duration of each component of the testing and isolation processes; length of stay; mean days in isolation and in hospital; and mean cost. We extracted data from hospital records and compared measures before and after implementation., Results: Clinicians ordered sputum testing for TB for 621 patients at ZSFG during the 2-year study period. Of 301 patients in the preimplementation period with at least 1 sputum microscopy and culture ordered, clinicians completed the rapid TB testing evaluation process for 233 (77%).Among 320 patients evaluated in the postimplementation period, clinicians ordered molecular testing for 234 (73%) patients and received results for 295 of 302 (98%) tests ordered. Median age was 54 years (interquartile range, 44-63 years), and 161 (26%) were women. The molecular testing algorithm accurately diagnosed all 7 patients with culture-confirmed TB and excluded TB in all 251 patients with Mycobacterium tuberculosis (MTB) culture-negative results. Compared with the preimplementation period, there were significant decreases in median times to final rapid test result (39.1 vs 22.4 hours, P < .001), discontinuation of isolation (2.9 vs 2.5 days, P = .001), and hospital discharge (6.0 vs 4.9 days, P = .003), on average saving $13 347 per isolated TB-negative patient., Conclusions and Relevance: A sputum molecular testing algorithm to guide discontinuation of respiratory isolation for patients undergoing evaluation for active TB was safe, feasible, widely and sustainably adopted, and provided substantial clinical and economic benefits. Molecular testing may facilitate more efficient, patient-centered evaluation for possible TB in US hospitals.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis., Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate., Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment., Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir., Clinical Trial Registration: NCT02738138.

Background: The objective of the study was to evaluate the role of a clinical pharmacist in hepatitis C virus (HCV) treatment of patients living with HIV/HCV coinfection., Methods: We conducted a descriptive study to quantify the functions of a clinical pharmacist in HCV treatment of patients living with HIV/HCV coinfection who were initiating HCV treatment at a publicly funded clinic between March 18, 2015 and September 15, 2016. The clinical pharmacist's role was categorized into eight categories: 1) HCV prior authorization (PA) completion; 2) HCV medication adherence counseling; 3) HCV drug-drug interaction (DDI) counseling and screening; 4) HCV medication counseling regarding common adverse events (AEs); 5) HCV counseling regarding HCV treatment outcomes and risk of reinfection; 6) ordering laboratory tests and interpretation of HCV laboratory values; 7) HIV medication AE assessment; and 8) other (including refilling medications and management of other comorbidities)., Results: One hundred and thirty-five patients initiated treatment during this timeframe: 77.0% were males, 56.3% non-cirrhotic, 77.0% HCV treatment-naïve, 45.9% HCV genotype 1a, and 83.0% initiated on ledipasvir/sofosbuvir. The clinical pharmacist completed 150 PAs, counseled on HCV medication adherence in 79.2% of patients, conducted HCV DDI counseling and screening in 54.2%, and monitored HCV medication AEs in 54.2%. The clinical pharmacist counseled patients on HCV treatment outcomes and risk of reinfection in 53.1%, ordered laboratory tests in 44.8%, and reported and interpreted laboratory values in 44.8%. The clinical pharmacist assessed HIV medication AEs in 54.2% of patients and participated in other activities in 42.7%., Conclusion: A clinical pharmacist's expertise as part of a multidisciplinary care team facilitates optimal treatment outcomes and provides critical support in the management of DAA therapy in individuals living with HIV/HCV coinfection., Competing Interests: Disclosure Parya Saberi has received a National Institute of Mental Health Grant (K23MH097649). Anne F Luetkemeyer has received research grant support to the University of California, San Francisco from AbbVie, Gilead, and Merck. The authors report no other conflicts of interest in this work.

Background & Aims: We report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens., Methods: The RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12 weeks of LDV/SOF or LDV/SOF + RBV. Compensated cirrhotic participants were randomized to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). Both studies used SVR at 12 weeks post-treatment (SVR12) as the primary endpoint., Results: In the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOF + RBV for 12 weeks and 80-92% in cirrhotic participants treated with LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic n = 1; GT1a n = 5) and all attained SVR12, with no serious AEs or premature discontinuations., Conclusions: In this SOF-experienced, NS5A inhibitor-naïve population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

At the 2018 Conference on Retroviruses and Opportunistic Infections (CROI), there was a major focus on hepatitis C virus (HCV) elimination and improving each component of the hepatitis C care cascade. Several countries and cohorts have demonstrated the remarkable impact that universal HCV testing and unrestricted access to hepatitis C treatment can have on markedly reducing incident HCV infections and HCV infection prevalence, including in people who inject drugs and HIV/HCV-coinfected populations. However, in many settings, substantial barriers to widespread HCV treatment remain, including undiagnosed HCV infection, particularly in populations outside the standard "baby boomer" birth cohort (ie, born 1945-1965); restricted access to hepatitis C treatment in those with known HCV infection; reinfection with HCV; and migration of HCV-infected populations. Many innovative programs have successfully implemented HCV testing and treatment outside of traditional care settings, expanding access for harder-to-reach populations, which will be crucial to successful elimination efforts. Outbreaks of hepatitis A virus (HAV) infection continue to occur in among men who have sex with men and homeless populations in the United States, Europe, and Southeast Asia, highlighting the need for improved HAV vaccination programs for populations at risk.

As a strategy to improve the sensitivity of nucleic acid-based testing in acid-fast bacilli (AFB) negative samples, larger volumes of sputum (5-10 mL) were tested with Xpert ® MTB/RIF from 176 individuals with smear-negative sputum undergoing tuberculosis evaluation. Despite larger volumes, this strategy had a suboptimal sensitivity of 50% (4/8)., Competing Interests: D.A. has received contracts for research from Cepheid, and is one of a group of coinvestigators who invented molecular beacon technology and who receive income from licensees, including a license to Cepheid for M. tuberculosis detection. However, the income attributable to the Xpert MTB/RIF assay which he may receive has been irrevocably capped at $5000 per year as a management of this conflict of interest. P.J. is an employee of Cepheid. D.A., D.A.B., C.F., and A.F.L. have received research grant support from Cepheid. All other authors report no potential conflicts.

Background: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis., Methods: TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks., Results: In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare., Conclusions: The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience.

Viral resistance to direct-acting antiviral drugs may impact their effectiveness during treatment of hepatitis C virus (HCV) infection. Most data on HCV drug resistance concern genotypes 1 and 3. The clinical impact of resistance to HCV nonstructural protein 5A (NS5A) inhibitors and a practical approach to indications and methods for resistance testing are discussed.

At the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, hepatitis C virus (HCV) infection was a major focus in the context of HIV-associated liver disease. Well-tolerated direct-acting antiviral (DAA) regimens have enabled effective treatment of the populations that are hardest to cure, including those with decompensated cirrhosis, and many studies examined the impact of HCV cure on hepatitis and extrahepatic outcomes. Scaling up access to DAA, and the impact that their universal availability can have on reducing prevalence were key topics. There was much discussion of what is needed to eliminate HCV on local and global levels and a focus on ensuring that the populations hardest to reach can access treatment. Prevention of new infections and reinfection will be key to sustaining the benefits of scaled-up HCV treatment, with particular attention to populations at elevated risk for HCV reinfection, including HIV-infected men who have sex with men (MSM) as well as some HIV-uninfected MSM on preexposure prophylaxis. In the hepatitis B virus (HBV) arena, a landmark phase III trial demonstrated that tenofovir disoproxil fumarate given to HBV-infected pregnant women at week 28 of gestation, in combination with postpartum HBV vaccination and hepatitis B immunoglobulin, resulted in zero mother-to-child transmissions of HBV.