<i>In Vitro</i>
            Evaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses

Marschall, Manfred; Stamminger, Thomas; Urban, Andreas; Wildum, Steffen; Ruebsamen‐Schaeff, Helga; Zimmermann, Holger; Lischka, Peter

doi:10.1128/aac.05908-11

Cited by 104 publications

(56 citation statements)

References 20 publications

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“…In fact, its novel mode of action not only appears to avoid the toxicities seen with the nucleoside analogues (19,20), but also offers new treatment options for patients infected with HCMV strains resistant to approved antivirals. The latter drug property is strongly supported by in vitro data, as well as initial clinical data relating to letermovir use in a lung transplant patient infected with a multiresistant HCMV strain (18,(22)(23)(24).…”

mentioning

confidence: 57%

In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

Wildum

Zimmermann

Lischka

2015

Antimicrob Agents Chemother

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H uman cytomegalovirus (HCMV) is a widespread opportunistic pathogen that rarely causes clinical manifestations in the healthy population; however, HCMV infection of immunocompromised individuals, such as transplant recipients or AIDS patients, is associated with serious and life-threatening diseases (1-3).In human stem cell transplant (HSCT) recipients, a primary infection with HCMV or reactivation of HCMV from persistently infected cells can lead to multiorgan disease, including hepatitis, pneumonia, gastroenteritis, and encephalitis, accounting for considerable mortality, particularly in HCMV-seropositive (R ϩ ) patients (4). After solid-organ transplantation (SOT), clinical disease is most common during primary HCMV infection of a seronegative individual receiving an organ from an HCMV-seropositive donor (D ϩ R Ϫ ). The most common clinical presentation is HCMV syndrome (fever, arthralgias, myalgias, and myelosuppression), though clinical disease may also present with evidence of end organ involvement, such as gastrointestinal disease or pneumonia, which is associated with increased morbidity and mortality and poor long-term outcomes after SOT (5, 6).HCMV is also the most common and most severe viral opportunistic infection in patients with HIV infection. Over 90% of all patients with HIV infection are seropositive for HCMV, and the virus can reactivate when the body's immune defenses are low, as can be seen in patients with AIDS (2). Before the availability of highly active antiretroviral therapy (HAART), up to 40% of HIVinfected patients developed HCMV disease, most commonly manifested as retinitis leading to blindness (7,8). Following initiation of HAART, the incidence of HCMV disease has decreased dramatically due to the reconstitution of humoral immunity against HCMV. However, for patients experiencing HAART failure (limited access to HAART, intolerable HAART regimens, poor compliance, or HIV resistance), the occurrence of HCMVassociated diseases remains a therapeutic challenge (2, 9, 10). In addition, evidence is emerging that accelerated aging and immunosenescence observed in HIV-HCMV-coinfected individuals during HAART is associated with asymptomatic HCMV replication (11,12).Current therapeutic options for the prevention and treatment of HCMV infections are limited to nucleoside analogues, e.g., oral or intravenous ganciclovir (GCV) or its oral prodrug, valganciclovir, together with the second-line treatments, foscarnet (FOS), cidofovir (CDV), and acyclovir (ACV) (the last drug is approved only for the prophylaxis of HCMV infections in SOT patients in a limited number of countries). Although these products are effective antivirals, all current treatments for HCMV are limited by dose-related toxicities, such as myelosuppression, neutropenia, and nephrotoxicity, which may eventually lead to treatment failure (3,13,14). Moreover, since all the drugs act by inhibiting the viral DNA polymerase pUL54, another treatment concern is the

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confidence: 57%

In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

Wildum

Zimmermann

Lischka

2015

Antimicrob Agents Chemother

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“…In line with its distinct mode of action, in vitro studies have shown that letermovir is active against HCMV strains resistant to current anti-HCMV drugs (4,5,7). In vivo confirmation of resistance-breaking potential was demonstrated in a patient infected with a multidrug-resistant HCMV strain (8).…”

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confidence: 87%

Geno- and Phenotypic Characterization of Human Cytomegalovirus Mutants SelectedIn Vitroafter Letermovir (AIC246) Exposure

Goldner

Hempel

Ruebsamen‐Schaeff

et al. 2014

Antimicrob Agents Chemother

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Letermovir is a novel antiviral compound currently in clinical development for the prevention of human cytomegalovirus (HCMV) infections. In contrast to all currently approved anti-HCMV drugs that target the viral DNA polymerase, letermovir acts via a distinct mode of action involving the viral terminase subunit pUL56. To extend our understanding of potential letermovir resistance mechanisms, we used marker transfer to characterize mutations identified in letermovir-resistant HCMV variants that were selected in cell culture. Human cytomegalovirus (HCMV) disease continues to be a serious and life-threatening condition in immunocompromised patients such as transplant recipients. Currently approved anti-HCMV drugs, including (val)ganciclovir, cidofovir, and foscarnet, are associated with profound toxicity as well as drug resistance that restricts their long-term clinical benefit. All these substances ultimately target the viral DNA polymerase (pUL54), though ganciclovir requires prior activation by the viral pUL97 kinase. Accordingly, mutations in open reading frame (ORF) UL97 are associated with (val)ganciclovir resistance whereas mutations in ORF UL54 can confer cross-resistance to all approved anti-HCMV drugs, an increasingly frequent scenario representing a serious threat for specific patient populations (1-3).Letermovir (AIC246) is a new anti-HCMV drug with a distinct but well-characterized mechanism of action targeting the viral terminase subunit pUL56 (4, 5). The drug has proven to be well tolerated in numerous (pre)clinical studies and has demonstrated clinical efficacy in a recent phase IIb trial, meeting all primary endpoints as a prophylactic drug (6).In line with its distinct mode of action, in vitro studies have shown that letermovir is active against HCMV strains resistant to current anti-HCMV drugs (4, 5, 7). In vivo confirmation of resistance-breaking potential was demonstrated in a patient infected with a multidrug-resistant HCMV strain (8). So far, no letermovir-resistant HCMV strains have been reported from clinical trials. Nonetheless, as letermovir is a direct-acting antiviral, the emergence of resistance is ultimately to be expected.HCMV resistance testing previously required virus cultivation and phenotypic characterization of virus isolates; this is slow, labor-intensive, and nonstandardized and often has a poor success rate (3, 9). Current standard clinical practice uses genotyping and virtual phenotyping based, e.g., on mutation databases (10). Once a database is established, this genetic approach is faster, more sensitive, and more cost-effective and provides detailed and quantitative resistance information to the physician (3). However, genetic monitoring of drug resistance requires detailed knowledge of potential resistance mutations in order to develop virtual phenotyping profiles for screening databases (6).To date, 2 letermovir resistance mutations leading to amino acid substitutions have been identified in vitro, both within the coding region for the pUL56 subunit of the viral termi...

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“…The clinical impact of drug-resistant CMV is enormous, as it has led to high rates of tissue-invasive disease, poor allograft survival, and heightened patient mortality (201,212). Treatment is very limited, and depending on the genetic profile, one may use highly nephrotoxic drugs, such as foscarnet and cidofovir (for UL97-exclusive mutants), or off-label and investigational drugs, such as leflunomide, maribavir, letermovir, and CMX-001 (201,(213)(214)(215).…”

Section: Relapse and Resistancementioning

confidence: 99%

Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation

2013

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SUMMARY The negative impact of cytomegalovirus (CMV) infection on transplant outcomes warrants efforts toward improving its prevention, diagnosis, and treatment. During the last 2 decades, significant breakthroughs in diagnostic virology have facilitated remarkable improvements in CMV disease management. During this period, CMV nucleic acid amplification testing (NAT) evolved to become one of the most commonly performed tests in clinical virology laboratories. NAT provides a means for rapid and sensitive diagnosis of CMV infection in transplant recipients. Viral quantification also introduced several principles of CMV disease management. Specifically, viral load has been utilized (i) for prognostication of CMV disease, (ii) to guide preemptive therapy, (iii) to assess the efficacy of antiviral treatment, (iv) to guide the duration of treatment, and (v) to indicate the risk of clinical relapse or antiviral drug resistance. However, there remain important limitations that require further optimization, including the interassay variability in viral load reporting, which has limited the generation of standardized viral load thresholds for various clinical indications. The recent introduction of an international reference standard should advance the major goal of uniform viral load reporting and interpretation. However, it has also become apparent that other aspects of NAT should be standardized, including sample selection, nucleic acid extraction, amplification, detection, and calibration, among others. This review article synthesizes the vast amount of information on CMV NAT and provides a timely review of the clinical utility of viral load testing in the management of CMV in solid organ transplant recipients. Current limitations are highlighted, and avenues for further research are suggested to optimize the clinical application of NAT in the management of CMV after transplantation.

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In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound AIC246 (Letermovir) against Herpesviruses and Other Human Pathogenic Viruses

Cited by 104 publications

References 20 publications

In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

Geno- and Phenotypic Characterization of Human Cytomegalovirus Mutants SelectedIn Vitroafter Letermovir (AIC246) Exposure

Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation

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