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.

Informing selection of drugs for COVID-19 treatment through adverse events analysis.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic and there is an urgent need for safe and effective drugs for COVID-19 treatment. Since developing a new drug is time consuming, many approved or investigational drugs have been repurposed for COVID-19 treatment in clinical trials. Therefore, selection of safe drugs for COVID-19 patients is vital for combating this pandemic. Our goal was to evaluate the safety concerns of drugs by analyzing adverse events reported in post-market surveillance. We collected 296 drugs that have been evaluated in clinical trials for COVID-19 and identified 28,597,464 associated adverse events at the system organ classes (SOCs) level in the FDA adverse events report systems (FAERS). We calculated Z-scores of SOCs that statistically quantify the relative frequency of adverse events of drugs in FAERS to quantitatively measure safety concerns for the drugs. Analyzing the Z-scores revealed that these drugs are associated with different significantly frequent adverse events. Our results suggest that this safety concern metric may serve as a tool to inform selection of drugs with favorable safety profiles for COVID-19 patients in clinical practices. Caution is advised when administering drugs with high Z-scores to patients who are vulnerable to associated adverse events.

No Association Between DAA Treatment for HCV Infection and Herpes Zoster Infection in Analysis of Data From 37 Clinical Trials.

BACKGROUND AND AIMS: Recent case series and retrospective studies have raised concerns that patients who receive direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection are at increased risk of developing varicella-zoster virus infection (VZV reactivation). We investigated the relationship between DAA treatment and VZV reactivation by analyzing pooled participant-level data from 37 clinical trials of DAA agents. METHODS: We obtained demographic, adverse event, and laboratory data from 13,816 participants in 37 clinical trials submitted to the Food and Drug Administration for approval of DAA agents for treatment of HCV infection. Participants received DAAs (n = 12,249), placebo (n = 997), pegylated interferon (n = 243), or a combination of DAAs and pegylated interferon (n = 327). Occurrence of VZV reactivation was identified using systematically reported adverse event data. HCV virologic response was evaluated by measurement of HCV RNA. RESULTS: VZV reactivation occurred in 9.9 cases per 1000 person-years of DAA treatment (95% CI, 6.8-14.0 per 1000 person years) and 13.8 cases per 1000 person-years of placebo (95% CI, 3.5-37.5 per 1000 person years). No participants in the pegylated interferon or combination DAA and pegylated interferon groups experienced VZV reactivation. Within the placebo-controlled trials there was no significant difference in VZV reactivation between DAA treatment and placebo. VZV reactivation was associated with age older than 40 years, female sex, and HIV coinfection. We did not find an association between time of virologic response and time to VZV reactivation. CONCLUSION: In an analysis of data from 37 trials, we found no evidence for an association between DAA treatment for HCV infection and increased risk of VZV reactivation.

Hepatitis C Virus RNA Levels Following Virologic Failure With Direct-acting Antivirals: Implications for Lower Sensitivity Diagnostic Assays.

We analyzed post-treatment hepatitis C virus (HCV) RNA levels from 330 subjects who experienced virologic failure in clinical trials of direct-acting antivirals. We demonstrated that 97% had post-treatment Week 12 HCV RNA >10 000 IU/mL, above reported sensitivity limits of novel diagnostic assays being considered for simplified HCV treatment monitoring.

Influenza A virus hemagglutinin mutations associated with use of neuraminidase inhibitors correlate with decreased inhibition by anti-influenza antibodies.

BACKGROUND: Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir. METHODS: NAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu- 3. RESULTS: We found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus. CONCLUSIONS: Although the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

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.

Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials.

Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed "resistant/refractory CMV" and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of "resistant" and "refractory" CMV. These definitions have emerged from the Working Group's review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.

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.

Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: Regulatory analyses and perspectives.

Several highly effective, interferon-free, direct-acting antiviral (DAA)-based regimens are available for the treatment of chronic hepatitis C virus (HCV) infection. Despite impressive efficacy overall, a small proportion of patients in registrational trials experienced treatment failure, which in some cases was associated with the detection of HCV resistance-associated substitutions (RASs) at baseline. In this article, we describe methods and key findings from independent regulatory analyses investigating the impact of baseline nonstructural (NS) 3 Q80K and NS5A RASs on the efficacy of current United States Food and Drug Administration (FDA)-approved regimens for patients with HCV genotype (GT) 1 or GT3 infection. These analyses focused on clinical trials that included patients who were previously naïve to the DAA class(es) in their investigational regimen and characterized the impact of baseline RASs that were enriched in the viral population as natural or transmitted polymorphisms (i.e., not drug-selected RASs). We used a consistent approach to optimize comparability of results across different DAA regimens and patient populations, including the use of a 15% sensitivity cutoff for next-generation sequencing results and standardized lists of NS5A RASs. These analyses confirmed that detection of NS3 Q80K or NS5A baseline RASs was associated with reduced treatment efficacy for multiple DAA regimens, but their impact was often minimized with the use of an intensified treatment regimen, such as a longer treatment duration and/or addition of ribavirin. We discuss the drug resistance-related considerations that contributed to pretreatment resistance testing and treatment recommendations in drug labeling for FDA-approved DAA regimens. CONCLUSION: Independent regulatory analyses confirmed that baseline HCV RASs can reduce the efficacy of certain DAA-based regimens in selected patient groups. However, highly effective treatment options are available for patients with or without baseline RASs. (Hepatology 2018;67:2430-2448).

US FDA Perspective on Elbasvir/Grazoprevir Treatment for Patients with Chronic Hepatitis C Virus Genotype 1 or 4 Infection.

Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.

Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir.

BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.

Resistance of human cytomegalovirus to ganciclovir/valganciclovir: a comprehensive review of putative resistance pathways.

Human cytomegalovirus (HCMV) is a pathogen that can be life-threatening in immunocompromised individuals. Valganciclovir and its parent drug ganciclovir are currently the principle drugs used for the treatment or prevention of HCMV disease. The development of HCMV resistance to ganciclovir/valganciclovir has been documented in treated patients and is associated with the emergence of amino acid substitutions in the viral proteins pUL97, pUL54 or both. Generally, single amino acid substitutions associated with clinical resistance that alone do not confer decreased ganciclovir susceptibility in cell culture have been disregarded as causative or clinically significant. This review focuses on the analysis and mechanisms of antiviral drug resistance to HCMV. We also conducted a review of publicly available clinical and nonclinical data to construct a comprehensive list of pUL97 and pUL54 amino acid substitutions that are associated with a poor clinical response to the first line therapies ganciclovir and valganciclovir, or associated with reduced HCMV ganciclovir susceptibility in cell culture. Over 40 putative ganciclovir/valganciclovir resistance-associated substitutions were identified in this analysis. These include the commonly reported substitutions M460I/V and C592G in pUL97. There were additional substitutions that are not widely considered as ganciclovir/valganciclovir resistance-associated substitutions, including V466M in pUL97 and E315D in pUL54. Some of these ganciclovir/valganciclovir resistance-associated substitutions may confer cross-resistance to other HCMV therapies, such as cidofovir and foscarnet. Based on this review, we propose that there are more potential HCMV ganciclovir/valganciclovir resistance pathways than generally appreciated. The resulting comprehensive list of putative ganciclovir/valganciclovir resistance-associated substitutions provides a foundation for future investigations to characterize the role of specific substitutions or combinations of substitutions, which will enhance our understanding of HCMV mechanisms of ganciclovir/valganciclovir resistance and also provide insight regarding the potential for cross-resistance to other HCMV therapies.