cmx-001 and Adenovirus-Infections--Human

Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great

Topics: Adenovirus Infections, Human; Animals; Antiviral Agents; Clinical Trials as Topic; Cytosine; DNA Virus Infections; DNA Viruses; Humans; Immunocompromised Host; Organophosphonates

In immunocompromised patients, human adenovirus (HAdV) infections can cause life-threatening multiorgan disease. This review summarizes the incidence and risk factors of invasive human adenovirus infections in immunocompromised patients as well as the recently developed standards for diagnostic methods and strategies according to the predominant risk factors in adults and children. Recommendations for preemptive and therapeutic treatment strategies and the outcome in different risk groups are presented. Novel therapeutic approaches including CMX001, a new orally bioavailable lipid conjugate of cidofovir and the transfer of adenovirus-specific donor T cells in the context of allogeneic stem cell transplantation are discussed.

Topics: Adenovirus Infections, Human; Adenoviruses, Human; Adult; Antiviral Agents; Child; Cytosine; Humans; Immunocompromised Host; Incidence; Organophosphonates; Risk Factors; Stem Cell Transplantation; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome; Viral Load

Human mastadenovirus (HAdV), a linear double-stranded DNA (dsDNA) virus, is the causal agent of several diseases, including pharyngoconjunctival fever, epidemic keratoconjunctivitis, and hemorrhagic cystitis, in immunocompromised individuals. There are more than 100 reported types of adenoviruses, but the pathogenicity of many HAdVs remains unknown. Brincidofovir (BCV) is a hexadecyloxypropyl lipid conjugate of cidofovir (CDV) that is active against dsDNA viruses. Clinical effectiveness of BCV against certain HAdV species has been reported; however, its activity against novel HAdV types remains unknown. We investigated the half-maximal inhibitory concentration (IC

Topics: Adenoviridae Infections; Adenovirus Infections, Human; Cystitis; Cytosine; Humans; Immunocompromised Host; Keratoconjunctivitis; Mastadenovirus; Organophosphonates

HAdV viremia can cause significant morbidity among pediatric recipients of SOT with variability in incidence and severity of disease based on the type of allograft. Currently, there are no US FDA-approved treatments for HAdV infections, and historically, the mainstay of treatment has been decreasing immunosuppression, with antiviral therapies reserved for those with severe disease. We describe the treatment of four pediatric SOT recipients (two kidney, one combined kidney-liver, and one liver) presenting with HAdV disease at our institution using brincidofovir. Our case series highlights the variability in presentation and the potential for severe disease in pediatric SOT recipients as we review disease presentation, disease course, complications, and treatment with brincidofovir.

Topics: Adenovirus Infections, Human; Adolescent; Antiviral Agents; Cytosine; Female; Follow-Up Studies; Humans; Infant; Kidney Transplantation; Liver Transplantation; Male; Organophosphonates; Postoperative Complications; Retrospective Studies; Transplant Recipients; Transplantation, Homologous; Young Adult

Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC

Topics: Adenovirus Infections, Human; Adenoviruses, Human; Antiviral Agents; Cidofovir; Cytosine; DNA Primers; DNA-Directed DNA Polymerase; DNA, Viral; Dose-Response Relationship, Drug; Humans; Kinetics; Mutation; Organophosphonates; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Viral Proteins; Virus Replication

Adenovirus infection is a well-known complication in patients receiving hematopoietic stem cell transplantation (HSCT). Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir, which has activity against adenoviruses. We present a review of adenovirus infections treated with BCV which were unresponsive to cidofovir initially in 4 patients and it was used upfront in one patient. Children with adenovirus infection following HSCT treated with BCV, between July 2014 and February 2018 were recognized. Five patients including 3 male and 2 female with a median age of 10 years (range, 2.2 to 10 y) were identified. The median days of adenoviremia detection was 18 days (range, 7 to 303 d) posttransplant. The median peak viral load by quantitative polymerase chain reaction was 21,38,000 copies/mL (range, 1,77,200 to 31,97,000 copies/mL). The median time from first detection of adenoviremia to become negative was 30 days (range, 15 to 113 d). The sites involved were gastrointestinal tract in all patients and 2 patients had additional respiratory tract involvement. Two patients survived and 3 patients died of sepsis. All patients responded well to BCV and no adverse effect was noticed. We saw the good safety profile and excellent antiadenoviral activity of BCV in pediatric patients receiving HSCT without the nephrotoxicity and it may have a role in preemptive therapy.

Topics: Adenovirus Infections, Human; Adolescent; Antiviral Agents; Child; Child, Preschool; Cytosine; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Male; Organophosphonates; Salvage Therapy; Viremia

Infections with adenovirus (AdV) and herpesviruses can result in considerable morbidity and mortality in pediatric hematopoietic stem cell transplant (SCT) recipients. Herpes simplex virus (HSV) reactivations are usually prevented by acyclovir (ACV) prophylaxis, whereas cidofovir (CDV) has been used off indication to manage AdV infections. We report a child with myelodysplastic syndrome undergoing multiple SCT, who experienced HSV-1 disease including severe mucositis and herpetic whitlow, as well as high viral load AdV DNAemia. Both ACV and CDV were ineffective; however, viral loads were decreased with brincidofovir, resulting in viral clearance. A subsequent Epstein-Barr virus disease with relevant meningoencephalitis responded to rituximab.

Topics: Acyclovir; Adenoviridae; Adenovirus Infections, Human; Antibiotic Prophylaxis; Antiviral Agents; Child, Preschool; Cidofovir; Cytosine; DNA, Viral; Drug Resistance, Viral; Epstein-Barr Virus Infections; Female; Foscarnet; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Herpes Zoster; Herpesvirus 1, Human; Herpesvirus 3, Human; Herpesvirus 4, Human; Humans; Immunocompromised Host; Meningoencephalitis; Mucositis; Myelodysplastic Syndromes; Organophosphonates; Rituximab; Viral Load

Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.

Topics: Adenovirus Infections, Human; Antiviral Agents; Child; Cytosine; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Organophosphonates; Polymerase Chain Reaction