#17,729
Antivirals - like antibiotics and antifungals - all have an Achilles' heel. Given enough time and usage, the pathogens (viruses, bacteria, or fungi) they were designed to defeat can evolve or mutate enough to render them ineffective.
In 2008 we watched seasonal H1N1 viruses go from being almost 100% sensitive to the drug Tamiflu (tm) to being nearly 100% resistant in a matter of months (see CIDRAP On the CDC Change Of Advice On Tamiflu).Sometimes, as we saw with M2 ion channel blockers (e.g. Amantadine, Rimantadine) used against influenza, that process can take decades. Sometimes, it happens much faster.
A bigger crisis was averted when a new pandemic H1N1 virus emerged in the spring of 2009 - supplanting the old strain - that retained sensitivity to the drug. Since then, resistance to Tamiflu has remained low (roughly 2%), but we monitor it closely for any changes.
Thirteen months ago, in FDA On The Potential For Monkeypox To Evade TPOXX (tecovirimat) Antivirals, we looked at concerns that an experimental antiviral - approved in 2018 for the treatment of human smallpox disease - could lose its effectiveness against Mpox.
The FDA warned:
For now, the vast majority of (pre-treatment) Mpox viruses remain susceptible to the TPOXX antiviral, but in some percentage of cases - most pronounced among immunocompromised individuals receiving extended treatment with the antiviral - resistance mutations have been detected.TPOXX works by inhibiting a viral protein, called VP37, that all orthopoxviruses (e.g., smallpox virus, monkeypox virus, vaccinia virus) share. However, as noted in the drug label, TPOXX has a low barrier to viral resistance. This means small changes to the VP37 protein could have a large impact on the antiviral activity of TPOXX.
Only rarely reported - some TPOXX resistant Mpox viruses have been identified in patients prior to treatment - but it remains unclear how common this might be.
Research
Tecovirimat Resistance in Mpox Patients, United States, 2022–2023
Todd G. Smith, Crystal M. Gigante, Nhien T. Wynn, Audrey Matheny, Whitni Davidson, Yong Yang, Rene Edgar Condori, Kyle O’Connell, Lynsey Kovar, Tracie L. Williams, Yon C. Yu, Brett W. Petersen, Nicolle Baird, David Lowe, Yu Li, Panayampalli S. Satheshkumar, and Christina L. Hutson
Abstract
During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.comExternal Link) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat.
Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype.
Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat.
Discussion
Multiple lines of evidence point to tecovirimat resistance developing during drug treatment in most patients.
First, genome sequencing has revealed unique mutational profiles from different sample sites from the same patient (Figure 2, panel A), indicating different viral subpopulations were selected at different sites during treatment.Second, longitudinal sampling was investigated for 4 of the 46 patients with a resistant isolate and showed samples before tecovirimat treatment were sensitive, whereas later samples were resistant (Figure 2, panel B).
An exception was found for 1 patient; T289A was detected in 58% of reads, along with minor populations of A295E (9%) and N267del (22%), from a sample the day before the patient started tecovirimat treatment. A second sample from the same patient after tecovirimat treatment showed the T289A mutation was selected (93%), and a new variant R291K was also detected (31%). In addition, N267del was detected in a cluster of cases in California with no known tecovirimat treatment (27).
Whether those drug-resistant infections were acquired from another person treated with tecovirimat is unknown but is a viable hypothesis. Such rare cases show that viruses with mutations in F13L resulting in tecovirimat resistance can be transmitted from person to person.
(SNIP)
Our results confirm that tecovirimat resistance mutations are being selected in human mpox patients by tecovirimat treatment. Resistance has been confirmed in a small percentage of cases, currently <1% of the total number of patients that have received tecovirimat.
Characteristics of patients with resistant isolates are very similar: uncontrolled HIV infection with very low CD4+ T-cell counts and potential for extensive tecovirimat exposure while hospitalized. The frequency of tecovirimat resistance may be higher in persons with uncontrolled HIV infection.
In rare cases, a drug-resistant virus appeared to have been transmitted to another person. Genomic and phenotype testing are ongoing. Our results may be useful when considering treatment for patients that match the clinical profile we described; aggressive early dosing and combination therapy regimens could be considered in those instances (21). Results will also provide critical knowledge to potentially build a genomic assay for early detection of resistance mutations which could be used to inform clinical care decisions.
For clinicians concerned about tecovirimat resistance, we encourage enrolling patients in the CDC VIRISMAP study (https://www.cdc.gov/poxvirus/mpox/clinicians/virismap.html) and the STOMP (Study of Tecovirimat for Mpox) trial (https://stomptpoxx.orgExternal Link)
In conclusion, we describe a large number of tecovirimat-resistant MPXV isolates from humans and provide crucial data on the amino acid changes leading to resistance in MPXV paired with clinical outcomes; these combined data may inform decisions on tecovirimat use in the future. Our findings also highlight the need for additional, well-tolerated OPXV therapeutics with different modes of action, particularly for use with immunocompromised patients.
Dr. Smith is a microbiologist in the Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Infectious Diseases, Centers for Disease Control and Prevention, in Atlanta, Georgia. His primary research interest is in smallpox preparedness.
DispatchCaitlin A. Contag
Abstract
Reports of tecovirimat-resistant mpox have emerged after widespread use of antiviral therapy during the 2022 mpox outbreak. Optimal management of patients with persistent infection with or without suspected resistance is yet to be established. We report a successfully treated case of severe mpox in California, USA, that had suspected tecovirimat resistance.
Tecovirimat is an antiviral drug approved in 2018 by the United States Food and Drug Administration to treat orthopoxvirus infection. Tecovirimat inhibits orthopoxvirus viral protein (VP) 37, which is involved in membrane formation required for egress-competent virions (1–3). Outside of a clinical trial, the Centers for Disease Control and Prevention recommends tecovirimat only for persons who have (or are at risk for) severe manifestations of mpox (4,5).
A low barrier to tecovirimat resistance by mutations in the VP37 protein encoded by the F13L gene of monkeypox virus (MPXV) has been demonstrated through in vitro and animal studies (6). Cases of suspected tecovirimat resistance during the ongoing mpox outbreak have occurred in immunocompromised patients receiving prolonged or repeated courses of tecovirimat (7,8).
More data are needed to inform the management of severe mpox, including cases of possible resistance. We report a case of a patient who had HIV/AIDS and prolonged severe mpox with F13L gene mutations concerning for possible tecovirimat resistance who was successfully treated with cidofovir, brincidofovir, and vaccinia immune globulin (VIGIV). Written consent was obtained from the patient to share all protected health information and images included in this case report.
Conclusions
During the ongoing multicountry mpox outbreak, mutations associated with tecovirimat resistance have been identified in immunocompromised patients who had severe or persistent mpox and a high mortality rate (7,8). It is unknown whether this patient was initially infected with a tecovirimat-resistant strain. However, resistance could have emerged during prolonged infection in this immunocompromised patient, who was receiving extended tecovirimat treatment, because 2 resistance mutations were detected in lesions sampled at different sites and timepoints. Different VP37 resistance mutations have been documented in separate lesions from persons who had severe mpox and underwent prolonged tecovirimat treatment (12). In addition, the patient might have had subtherapeutic tecovirimat serum concentrations and subsequent selection for resistance when he took his initial course of tecovirimat without high-fat meals (ideally 600 calories or 25 g of fat) (13). Challenges for patients living with advanced HIV infection often include lack of housing (14) and access to regular food sources, which can pose additional burdens to the specific dietary requirements for tecovirimat absorption (4,15).
Both the failure to recognize the lesions as progressive mpox and delayed HIV diagnosis probably contributed to the severity of disease in this patient. Current guidelines advise that screening for sexually transmitted infections and HIV be offered to all sexually active patients who have mpox (https://www.cdc.gov/poxvirus/mpox/clinicians/people-with-HIV.html). Earlier ART initiation would probably have benefited the patient. Clinicians caring for patients who have persistent mpox should evaluate for underlying immunodeficiency, particularly HIV, and consider the possibility of antiviral resistance in cases that fail to respond to standard of care. WGS is helping to illuminate the potential resistance mutations that might occur in mpox cases, as well as describe the genetic differences between strains. However, MPXV WGS data are not approved for clinical use, and there is a paucity of data guiding the clinical application of MPXV sequencing. With the likelihood for continued human-to-human transmission of MPXV, expert consultation should be sought for patients who have nonresolving mpox, and lesion samples should be obtained for genotypic and phenotypic resistance testing to inform future case management.
Dr. Contag is an infectious diseases and critical care fellow at Stanford University, Palo Alto, California. Her primary research interests are emerging and reemerging infectious diseases and the management of critical illness in low-resource settings.
Whether it is vaccines, antibiotics, or antivirals, we are engaged in an endless `arms race' with countless thousands of constantly evolving pathogens whose very survival depends on evading our medical armamentarium.
Pharmacological victories can be fragile, and are often fleeting.
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While I cover AMR topics occasionally in this blog, I can heartily recommend CIDRAP's Antimicrobial Stewardship Project as the best place to learn about the growing global threat of AMR.
