Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

Long-Acting Formulations for the Prevention and Treatment of Human Immunodeficiency Virus (HIV)-1 Infection: Strategic Leveraging and Integration of Multidisciplinary Knowledge to Advance Public Health.

The landscape for the development of therapeutics for prevention and treatment of human immunodeficiency virus (HIV)-1 infection has pivoted towards long-acting antiretrovirals (LA-ARVs). LA-ARVs have the potential to transform global implementation of HIV-1 prevention and treatment strategies. The ability to identify potential knowledge gaps early in development, proactively address missing information or data gaps, and strategically leverage all the available information is the key to streamline the development of safe and effective LA-ARV therapeutics. The purpose of this article is to discuss some potential considerations for development of LA-ARVs. Three possible drug development scenarios are briefly discussed and include developing (1) a novel LA-ARV, (2) a novel LA formulation of an approved oral ARV, and (3) an LA pro-drug of an approved oral ARV. For each of these scenarios, we briefly describe what type(s) of information may be helpful and discuss potential opportunities to leverage available information. Additionally, we discuss some unique LA-ARV drug development considerations, including the use of an oral lead-in, and assessing the impact of residual ARV exposures on subsequent regimens and evaluation of LA-ARVs in specific populations. We strongly believe that efficient integration of multidisciplinary knowledge can advance the development, availability, and accessibility of therapeutics not only for HIV-1 prevention and treatment but also for other chronic viral infections.

Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials.

BACKGROUND: BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. RESULTS AND DISCUSSION: Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. METHODS: To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. CONCLUSIONS: These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients.

Drug Development 101: A Primer.

Drug development is a term used to define the entire process of bringing a new drug or device to market. It is an integrated, multidisciplinary endeavor that includes drug discovery, chemistry and pharmacology, nonclinical safety testing, manufacturing, clinical trials, and regulatory submissions. This report summarizes presentations of a workshop entitled "Drug Development 101," held at the 39th Annual Meeting of the American College of Toxicology in West Palm Beach, Florida. The workshop was designed to provide an introductory overview of drug development. Experienced scientists from industry and government provided overviews of each area, with a focus on safety assessment, and described some of the challenges that can arise. The role of chemistry and manufacturing was discussed in the context of early- and late-stage product development and approaches to assess, control, and limit impurities. The toxicologic assessment was emphasized in early-phase development, from the selection of a candidate drug through the determination of a first-in-human starting dose. Clinical trial development was discussed in the context of regulatory requirements and expectations. The final topic of issues and considerations in the review processes of different types of submissions to Food and Drug Administration included advice for best practices in authoring good Investigational New Drug and New Drug Application/Biologic License Application submissions and interacting effectively with regulatory reviewers.

The Development of Therapeutics for the Treatment and Prevention of CMV Disease in the Transplant Population: A Regulatory Perspective.

Cytomegalovirus (CMV) remains an important pathogen in the transplant population. As such, the US Food and Drug Administration has published a guidance to encourage and inform the development of therapeutics for the treatment and prevention of CMV disease in this population. This review summarizes important phase 3 trial design considerations for industry and provides rationale for some of the recommendations included in the guidance.

In-depth genomic analyses identified novel letermovir resistance-associated substitutions in the cytomegalovirus UL56 and UL89 gene products.

Letermovir is a human cytomegalovirus (HCMV) terminase inhibitor recently approved in the United States for prophylaxis of HCMV infection or disease in adult HCMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant. In the registrational trial, the rate of clinically significant HCMV infection, defined as the development of HCMV DNAemia leading to preemptive antiviral therapy or the diagnosis of HCMV end-organ disease, through 24 weeks post-transplant, was significantly lower among subjects who received letermovir prophylaxis through 14 weeks post-transplant compared to those who received placebo. We performed independent analyses of the HCMV nucleotide sequencing data generated by next-generation sequencing from this phase 3 registrational trial of letermovir to identify viral genetic characteristics associated with virologic failure during and following letermovir prophylaxis. The pUL56 substitutions V236M, E237G, and C325W, identified at previously known resistance-associated positions, were detected in the virus of subjects who were treated with letermovir and failed letermovir prophylaxis. Several additional substitutions were detected in pUL56 and pUL89, and further characterization is needed to determine if any of these substitutions are clinically relevant. The analyses reported herein were conducted to confirm sponsor-reported drug-resistance pathways, to assess the frequency of resistance, and to better understand the risk of prophylaxis failures and treatment-emergent drug resistance.

Increased CMV IgG Antibody Titer is Associated with Non-AIDS Events among Virologically Suppressed HIV-Positive Persons.

BACKGROUND: Among HIV-positive individuals, increased levels of inflammation and immune activation persist even in the setting of effective antiretroviral therapy (ART) and are associated with greater rates of non-AIDS events. The etiology of this persistent inflammation is incompletely understood. METHODS: Using a well-characterized cohort of 322 HIV-infected individuals on suppressive ART, we conducted a case-control study. Cytomegalovirus (CMV) immunoglobulin G (IgG) levels, plasma biomarkers, and T-cell phenotypes were measured/characterized from samples collected 1 year after ART initiation. Conditional logistic regression for matched case-control studies analyzed the associations of year 1 CMV-specific IgG level with the subsequent occurrence of any non-AIDS event. Correlations between continuous CMV IgG antibody levels and soluble and cellular markers were assessed. RESULTS: We found that higher levels of CMV IgG were associated with increased risk of non-AIDS events (OR = 1.58 per IQR [95% CI: 1.12, 2.24], P = 0.01) and with elevated soluble and cellular markers of inflammation. CONCLUSIONS: The magnitude of the host immune response to CMV may play a role in the persistent inflammation and resultant morbid events observed in the HIV-positive population.

Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives.

This review summarizes the significant impact of cytomegalovirus (CMV) infection on solid organ and hematopoietic stem cell transplant recipients. A discussion of the various CMV prevention and treatment strategies is provided, including a detailed description of each of the available CMV antiviral drugs.

Poor positive predictive value of influenza-like illness criteria in adult transplant patients: a case for multiplex respiratory virus PCR testing.

BACKGROUND: Respiratory viral infections (RVIs) are a significant cause of morbidity and mortality among transplant patients. The CDC's influenza-like illness (ILI) criteria (fever ≥100°F with cough and/or sore throat) are a screening tool for influenza with unknown applicability to the transplant population. METHODS: We reviewed all respiratory virus PCR tests performed on adult patients with a history of solid organ (SOT) or stem cell transplantation (HSCT) during the 2012-2013 influenza season. The positive (PPV) and negative predictive values (NPV) of ILI criteria were calculated. RESULTS: Of 126 transplant patients (66 HSCT, 60 SOT), 54 (42.8%) tested positive for an RVI by PCR: 24 influenza and 30 non-influenza. Of 30 patients who met ILI criteria, 12 (40%) were positive for influenza. The PPV and NPV of ILI for influenza were 50% and 82.4%, respectively. Mortality was low (3.7%), but morbidity was high (14.8% required ICU stay) among transplant patients diagnosed with RVI. CONCLUSIONS: Influenza and non-influenza RVIs are associated with significant morbidity among transplant patients. CDC ILI criteria correlate poorly with PCR-positive cases of influenza in transplant patients, but may be useful in excluding the diagnosis. Routine RVI PCR testing is recommended for better diagnosis and improved antiviral use in transplant patients with suspected RVI.

A matched cross-sectional study of the association between circulating tissue factor activity, immune activation and advanced liver fibrosis in hepatitis C infection.

BACKGROUND: Tissue factor (TF) is a protein that mediates the initiation of the coagulation cascade. TF expression is increased in patients with poorly-controlled HIV, and may be associated with increased immune activation that leads to cardiovascular morbidity. The role of TF in immune activation in liver disease in hepatitis C virus (HCV)-monoinfection and HIV/HCV-coinfection has not been explored. METHODS: Fifty-nine patients were stratified: A) HIV-monoinfection (N = 15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N = 15), C) HIV/HCV-coinfection with CHC (N = 14), and D) HIV/HCV-seropositive with cleared-HCV (N = 15). All HIV+ patients had undetectable HIV viremia. Whole blood was collected for CD4/CD8 immune activation markers by flow cytometry and plasma was assayed for microparticle TF (MPTF) activity. Subjects underwent transient elastography (TE) to stage liver fibrosis. Undetectable versus detectable MPTF was compared across strata using Fisher's Exact test. RESULTS: MPTF activity was more frequently detected among patients with HCV-monoinfection (40%), compared to HIV-monoinfection and HIV/HCV-seropositive with cleared HCV (7%) and HIV/HCV-coinfection with CHC (14%) (p = 0.02). Mean TE-derived liver stiffness score in kPa was higher in patients with detectable MPTF (12.4 ± 8.5) than those with undetectable MPTF (6.4 ± 3.0) (p = 0.01). Mean CD4 + HLADR+ and CD4 + CD38-HLADR+ expression were higher in those with detectable MPTF (44 ± 9.8% and 38 ± 8.7%, respectively) than those with undetectable MPTF (36 ± 11% and 31 ± 10.4% respectively) (p = 0.05 and 0.04 respectively). CONCLUSIONS: HCV-monoinfection and HIV/HCV-coinfection with CHC were associated with MPTF activity. MPTF activity is also associated with advanced liver fibrosis and with CD4 + HLADR+ immune activation.

Characterization of CD4⁺ T-cell immune activation and interleukin 10 levels among HIV, hepatitis C virus, and HIV/HCV-coinfected patients.

BACKGROUND: HIV/hepatitis C virus (HCV)-coinfected patients have accelerated liver disease compared with HCV monoinfection. In HIV-positive patients with viral suppression, data comparing inflammatory cytokines and immune activation between HIV/HCV coinfection with chronic hepatitis C (CHC) to HIV/HCV-seropositive patients with cleared HCV are limited. METHODS: Fifty-nine age- and sex-matched patients were stratified: (1) HIV monoinfection (n = 15); (2) HCV monoinfection with CHC (n = 15); (3) HIV/HCV coinfection with CHC (n = 14); and (4) HIV/HCV seropositive with cleared HCV (n = 15). All HIV-positive patients had undetectable HIV viremia, and median CD4 was 420 cells per microliter. Liver fibrosis was assessed in each subject using transient elastography. Cells were collected for CD4 and CD8 immune activation (CD38/HLA-DR) markers via flow cytometry and plasma for luminex-multiplex cytokine assays. RESULTS: CD38⁺HLA-DR⁺ expression on CD4⁺ T cells was significantly increased in HIV/HCV coinfection with CHC (7%) versus HCV monoinfection (4%) (P = 0.012). CD4⁺ total HLA-DR⁺ expression was significantly increased in HIV/HCV coinfection with CHC (43%) versus HIV monoinfection (31%) (P = 0.010) and HIV/HCV seropositive with cleared HCV (38%) (P = 0.046). Total CD4⁺CD38⁺ and CD4⁺CD38⁺HLA-DR⁻ expression was significantly higher in HIV monoinfection (23% and 18%) than HCV moninfection (13%, P = 0.002% and 9%, P = 0.001, respectively). Interleukin 10 levels were significantly lower in HIV monoinfection versus HIV/HCV coinfection with CHC (P = 0.0002). In multivariate analysis, severe fibrosis was associated with lower expression of CD4⁺CD38⁺HLA-DR⁺ and CD4⁺ total CD38⁺ than mild-moderate fibrosis (P = 0.03 and 0.03, respectively). CONCLUSIONS: CD4 immune activation with HLA-DR⁺ expression in HIV/HCV coinfection with well-controlled HIV may arise from chronic HCV viremia. Conversely, CD4⁺CD38⁺ expression may be driven by underlying HIV infection. CD4 immune activation was unexpectedly found to be associated with decreased liver fibrosis.

Thalidomide-associated thrombosis in the treatment of HIV-associated severe aphthous disease: a case report and review of the literature.

Venous thrombosis is a well-described complication of thalidomide therapy in patients with multiple myeloma (MM). However, an association between thalidomide use and thrombosis in HIV-positive patients has not been previously described. We present the case of a 48-year-old HIV-positive man who developed a deep venous thrombosis while on thalidomide for the treatment of severe aphthous ulcers. We review the management of severe aphthous disease and the potential adverse effects of thalidomide therapy. We examine the association between thalidomide and thrombosis in patients with MM and discuss how the same relationship may or may not exist in HIV-positive patients. Although the strength of the association between thalidomide use and thrombosis in HIV-positive patients being treated for aphthous disease remains unclear, HIV providers should be aware of the potential risk of thrombosis in all patients receiving thalidomide.

Prevalence of asymptomatic bacterial sexually transmitted infections in hospitalized HIV patients in Baltimore City.

Sexually transmitted infections (STIs) are known to promote the transmission of HIV. Diagnosing these infections can identify patients engaging in high-risk behaviors and provides an opportunity for intervention and education. The Centers for Disease Control and Prevention (CDC) recommends STI screening as part of routine HIV care. Ninety HIV-infected inpatients admitted to the University of Maryland Hospital were screened for gonorrhea, chlamydia, and syphilis. None of the nucleic acid amplification probes were positive for gonorrhea, and 1 was positive for chlamydia. A total of 8 rapid plasma reagin (RPR) tests were positive, 2 of which are believed to be associated with new infection or treatment failure. Rapid plasma reagin positivity was found to be associated with men who have sex with men (MSM), low CD4 count, and high HIV viral load. Routine inpatient screening for asymptomatic STIs in HIV-infected patients may be beneficial, particularly patients not engaged in routine outpatient care.