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Drug Resistance Updates : Reviews and... Mar 2018Herpesviruses thymidine kinase (TK) and protein kinase (PK) allow the activation of nucleoside analogues used in anti-herpesvirus treatments. Mutations emerging in these... (Review)
Review
Herpesviruses thymidine kinase (TK) and protein kinase (PK) allow the activation of nucleoside analogues used in anti-herpesvirus treatments. Mutations emerging in these two genes often lead to emergence of drug-resistant strains responsible for life-threatening diseases in immunocompromised populations. In this review, we analyze the binding of different nucleoside analogues to the TK active site of the three α-herpesviruses [Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2) and Varicella-Zoster Virus (VZV)] and present the impact of known mutations on the structure of the viral TKs. Furthermore, models of β-herpesviruses [Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6)] PKs allow to link amino acid changes with resistance to ganciclovir and/or maribavir, an investigational chemotherapeutic used in patients with multidrug-resistant HCMV. Finally, we set the basis for the understanding of drug-resistance in γ-herpesviruses [Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV)] TK and PK through the use of animal surrogate models.
Topics: Animals; Antiviral Agents; Drug Design; Drug Resistance, Viral; Herpesviridae; Herpesviridae Infections; Humans; Mutation; Protein Conformation; Protein Kinases; Structure-Activity Relationship; Thymidine Kinase; Viral Proteins
PubMed: 29548479
DOI: 10.1016/j.drup.2018.01.003 -
Antiviral Research Apr 2020Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase... (Review)
Review
Cytomegalovirus (CMV) drug resistance mutation maps are updated with recent information for polymerase inhibitors, the terminase inhibitor letermovir and the UL97 kinase inhibitor maribavir. Newly mapped mutations and their phenotypes provide more detail on cross-resistance properties and suggest the need to expand the CMV gene regions covered in diagnostic testing. Next-generation deep sequencing technology offers a more sensitive, higher resolution view of emerging antiviral resistance and is recommended for use in clinical trials. Issues of standardization and diagnostic utility in comparison with traditional Sanger sequencing remain unresolved. Quality control is important for the accurate and reproducible detection of mutant viral populations in clinical specimens.
Topics: Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Multiple, Viral; Genotype; Genotyping Techniques; High-Throughput Nucleotide Sequencing; Humans; Mutation; Viral Proteins
PubMed: 31940472
DOI: 10.1016/j.antiviral.2020.104711 -
Cancers Jun 2018Epstein⁻Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic....
Epstein⁻Barr virus (EBV) infects up to 95% of the adult human population, with primary infection typically occurring during childhood and usually asymptomatic. However, EBV can cause infectious mononucleosis in approximately 35⁻50% cases when infection occurs during adolescence and early adulthood. Epstein⁻Barr virus is also associated with several B-cell malignancies including Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. A number of antiviral drugs have proven to be effective inhibitors of EBV replication, yet have resulted in limited success clinically, and none of them has been approved for treatment of EBV infections.
PubMed: 29899236
DOI: 10.3390/cancers10060197 -
Clinical Infectious Diseases : An... Jul 2021Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of...
Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of these drugs is limited by toxicity and the development of resistance. The 2017 approval of letermovir for prevention of CMV after stem cell transplant marked the first approval of an anti-CMV agent since 2003. The role of letermovir in treatment of established CMV infection or disease remains largely unstudied, although early reports suggest that a low barrier to resistance will likely limit efficacy as primary therapy for patients with refractory or resistant disease. The investigational agent maribavir has shown promise as preemptive treatment; in patients with refractory or resistant disease the emergence of resistance while on treatment has been observed and ongoing studies will define efficacy in this population. Both agents have unique mechanisms of action limiting cross resistance, and neither exhibit myelotoxicity or nephrotoxicity.
Topics: Acetates; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Humans; Quinazolines; Ribonucleosides; Transplant Recipients
PubMed: 33197929
DOI: 10.1093/cid/ciaa1713 -
Current Hematologic Malignancy Reports Apr 2020CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often... (Review)
Review
PURPOSE OF REVIEW
CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.
RECENT FINDINGS
Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy; Opportunistic Infections; Risk Factors; T-Lymphocytes; Treatment Outcome
PubMed: 31981100
DOI: 10.1007/s11899-020-00557-6 -
Expert Review of Hematology Jun 2016Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared... (Review)
Review
Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.
Topics: Animals; Antiviral Agents; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; T-Lymphocytes; Transplantation, Homologous; Treatment Outcome
PubMed: 27043241
DOI: 10.1080/17474086.2016.1174571 -
Annals of Hematology Aug 2023
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Transplant Recipients
PubMed: 37183208
DOI: 10.1007/s00277-023-05265-8 -
Expert Review of Clinical Pharmacology Oct 2018Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with... (Review)
Review
Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries. Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities. Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis.
Topics: Acetates; Adult; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Quinazolines; Serologic Tests; Virus Activation
PubMed: 30004790
DOI: 10.1080/17512433.2018.1500897 -
Expert Opinion on Drug Safety Nov 2019: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and... (Review)
Review
: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell transplantation. : This review discusses the safety profiles of currently available and emerging antiviral drugs and the other strategies for HCMV prevention and treatment after transplantation. : Strategies for management of HCMV rely largely on the use of antiviral agents that inhibit viral DNA polymerase (ganciclovir/valganciclovir, foscarnet, and cidofovir/brincidofovir) and viral terminase complex (letermovir), with different types and degrees of adverse effects. An investigational agent, maribavir, exerts its anti-CMV effect through UL97 inhibition, and its safety profile is under clinical evaluation. In choosing the antiviral medication to use, it is important to consider these safety profiles in addition to overall efficacy. In addition to antiviral drugs, reduction of immunosuppression is often generally needed in the management of HCMV infection, but with a potential risk of allograft rejection or graft-versus-host disease. The use of HCMV-specific or non-specific intravenous immunoglobulins remains debated, while adoptive HCMV-specific T cell therapy remains investigational, and associated with unique set of adverse effects.
Topics: Antiviral Agents; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Opportunistic Infections; Organ Transplantation
PubMed: 31478398
DOI: 10.1080/14740338.2019.1662787