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Background: Among 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug., Methods: Viral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment., Results: Prior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug., Conclusion: After 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy., Clinical Trials Registration: NCT02927067 (AURORA)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. G. A. P. reports research funding (paid to their institution) from Merck and Takeda; consulting fees from Merck, Symbio, and Takeda; honoraria from Merck; serving on a data and safety monitoring board or advisory board for AlloVir, Armata, and Vera; and serving as chair (voluntary) for the Transplant Infectious Disease of the American Society for Transplantation and Cellular Therapy. R. K. A. reports study/grant support (paid to their institution) from AiCuris, Astellas, AstraZeneca, Chimerix, Merck, Moderna, Oxford Immunotec, Qiagen, Regeneron, and Takeda. C. C. reports study/grant support (paid to their institution) from Merck Sharp & Dohme and Takeda; consulting fees from Takeda; and honoraria (personal) from Takeda and Merck Sharp & Dohme. R. F. D. reports consulting fees (advisor honoraria) from Cidara, Gilead Sciences, Jazz Pharmaceuticals, Merck Sharp & Dohme, Omeros Corporation, and Sobi; honoraria (speaker's bureau) from Bristol Myers Squibb, Gilead Sciences, Jazz Pharmaceuticals, Merck Sharp & Dohme, Omeros Corporation, and Takeda; support for attending meetings and/or travel from Bristol Myers Squibb, Gilead Sciences, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Omeros Corporation, and Pfizer; and receipt of equipment and materials from Roche Diagnostics. S. H. reports honoraria (advisory board) from Takeda. J. M. reports honoraria (speaker) and advisory board participation from Takeda; consulting fees from F2G, Gilead Sciences, Mundipharma, and Pfizer; honoraria from F2G, Gilead Sciences, Mundipharma, and Pfizer; support for attending meetings and/or travel from F2G, Gilead Sciences, and Mundipharma; and serving on a data and safety monitoring board or advisory board for Cidara, F2G, Gilead Sciences, Mundipharma, and Takeda. C. S. reports honoraria (speaker) from GSK, Merck Sharp & Dohme, and Pfizer and support for attending meetings and/or travel to an American Society of Hematology Annual Meeting from Kite Pharma, a Gilead company. J.-A. H. Y. reports trial reimbursement (paid to their institution) from Takeda and serving as editor-in-chief for Clinical Microbiology Reviews and as associate editor (unpaid) for Transplantation and Cellular Therapy. M. F., J. W., R. A. M. and T. B. report employee and stock/stock options from Takeda. D. J. W. reports research grants from Ansun Biopharma, Cidara, Symbio, and Takeda and consulting fees from Shire and ViroPharma. The remaining author reports 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.

Background: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir., Methods: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed., Results: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%)., Conclusions: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA]., Competing Interests: Potential conflicts of interest. G. A. P.—research funding (paid to their institution): Merck, Takeda; consulting fees: Merck, Symbio, Takeda; honoraria: Merck; data safety monitoring board or advisory board: AlloVir, Armata, Vera; chair (voluntary): Transplant Infectious Disease of the American Society for Transplantation and Cellular Therapy (ASTCT). R. K. A.—study/grant support (paid to their institution): AiCuris, Astellas, AstraZeneca, Chimerix, Merck, Oxford Immunotec, Qiagen, Regeneron, Takeda. C. C.—study/grant support (paid to their institution): Merck Sharp & Dohme, Takeda; consulting fees: Takeda; honoraria (personal): Takeda, Merck Sharp & Dohme. R. F. D.—consulting fees (advisor honoraria): Cidara, Gilead Sciences, Jazz Pharmaceuticals, Merck Sharp & Dohme, Omeros Corporation, Sobi; honoraria (speaker’s bureau): Bristol Myers Squibb, Gilead Sciences, Jazz Pharmaceuticals, Merck Sharp & Dohme, Omeros Corporation, Takeda; support for attending meetings and/or travel: Bristol Myers Squibb, Gilead Sciences, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Omeros Corporation, Pfizer; receipt of equipment and materials: Roche Diagnostics. S. H.—honoraria (advisory board): Takeda. J. M.—honoraria (speaker) and advisory board participation: Takeda; consulting fees: F2G, Gilead Sciences, Mundipharma, Pfizer; honoraria: F2G, Gilead Sciences, Mundipharma, Pfizer; support for attending meetings and/or travel: F2G, Gilead Sciences, Mundipharma; data safety monitoring board or advisory board: Cidara, F2G, Gilead Sciences, Mundipharma, Takeda. C. S.—honoraria (speaker): GSK, Merck Sharp & Dohme, Pfizer; support for attending meetings and/or travel to American Society of Hematology Annual Meeting: Kite Pharma, a Gilead company. J.-A. H. Y.—trial reimbursement (paid to their institution): Takeda; Editor in Chief (completed 30 June 2022): Clinical Microbiology Reviews; Associate Editor (unpaid): Transplantation and Cellular Therapy. M. F., J. W.—employee and stock/stock options: Takeda. R. A. M.—employee: Takeda. D. J. W.—research grants: Ansun Biopharma, Cidara, Symbio, Takeda; consulting fees: Shire, ViroPharma. K. S. P. reports 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.)

Objectives: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT., Methods: Patients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin)., Results: Mean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable)., Conclusions: Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk., Trial Registry and Number: ClinicalTrials.gov, NCT01075984., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials., Methods: Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada., Results: Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%)., Conclusions: DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection--individuals for whom real-world data are urgently needed., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety., Methods: Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36., Results: Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure., Conclusions: In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-to-platelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC)., Methods: Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC. Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent., Results: A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%)., Conclusions: Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV-coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Right-sided endocarditis (RSE) is a serious complication of intravenous drug use. We sought to systematically review the evidence for obtaining clinical cure with antimicrobials in intravenous drug users (IVDUs) with isolated native valve RSE., Search Strategy: We applied broad search strategies in the following databases: MEDLINE (1966-2006), EMBASE (1980-2006) and Cochrane CENTRAL Register (2006, Issue 3). Hand searching was performed on selected peer-reviewed journals and relevant citation lists were screened. No restrictions were set on language and type of publication., Selection Criteria: We included randomized controlled trials that evaluated clinical and microbiological cure using single or combination antibiotic regimens for the treatment of isolated native valve bacterial RSE. Clinical and microbiological cure and failure outcomes were evaluated between 2 weeks and 6 months after completion of therapy. Quality assessment of relevant studies was performed using an objective scoring scale., Results: We identified seven randomized controlled trials, one comparing single antimicrobial therapies, four comparing combination with single therapy and two studies comparing combination therapies. Short-course therapy was present in at least one arm in three studies, but only one study compared short- and long-course therapy. No statistically significant benefit was demonstrated between any antimicrobial therapy and all studies were scored as having a moderate to severe risk of bias., Conclusions: Randomized trial evidence does not support one antimicrobial regimen over another in the treatment of RSE in IVDUs.