Summary
- For those families living with a diagnosis of feline infectious peritonitis (FIP) and for the veterinarians involved in their care, we understand that the decision to pursue the use of unlicensed therapy for what is otherwise an invariable fatal disease presents an ethical dilemma.
- We strongly caution against widespread use of single-agent antiviral therapy in catteries and shelters with endemic feline enteric coronavirus (FECV). Broad use in such settings is expected to generate antiviral resistant FIP strains.
- In cases where treatment is pursued, we recommend cat owners work with their veterinarian to ensure an accurate diagnosis (AAFP guidelines) and to have their pet monitored continually during the treatment process. Information on clinical trials can be found at: https://www.fipvetguide.com/studies
Position Statement (2024)
Test to treat
As many of you many know, the Whittaker lab has been researching feline coronavirus and feline infectious peritonitis (or FIP) for around a decade now, and using this information to develop new sequencing-based tests for this devastating disease of cats. But this journey has been complicated. Very interesting and informative, but more complicated than we ever imagined.
Our journey has made me realize that we need think about FIP in cats in the same way we think about HIV and AIDS in humans. I want to stress that these are quite different viruses from a mechanistic perspective, but may be quite similar conceptually. The concept is that both are long-term infections of their respective hosts, they have complicated biology and evolution of the virus within and between hosts. This complex disease process drives the need for sequencing-based approaches for diagnostics, as opposed to the more traditional PCR-based approaches typically used for infectious diseases. Other commonalties, include the lack of an effective vaccine, and the availability of anti-viral drugs to manage both individual clinical cases and spread within the community.
For FIP, the past year or two have been transformational, with the now widespread use of antiviral drugs to treat this once-deadly disease. Several compounds are now in use by the public, but this is not under good regulatory or clinical management and largely occurring in the absence of good viral diagnostics. This is in direct contrast to HIV/AIDS where robust test-to-treat procedures are part of clinical care for patients and now expanding to a community-wide strategy of what is known as ‘universal test and connect”. One key part of these HIV programs is to monitor for drug resistance. Antimicrobial drug resistance (or AMR) is more widely appreciated in the context of the antibiotics used for bacterial infections, but is also important for viruses and anti-virals (where it is called AVR). This is hugely important for HIV/AIDS; and while coronaviruses may have a higher barrier to development of drug-resistant mutants than HIV does, AVR can and does occur. Currently this is not well-tracked in coronavirus-infected patients.
Another major change in the world of FIP occurred this past summer, when a large outbreak of FIP-like disease was recognized in Cyprus, a Mediterranean island with a big and largely outdoor cat population. This is now known to be caused by a novel feline-canine recombinant virus. Unlike more traditional FIP viruses, there is likelihood of efficient spread of these novel strains between animals, possibly even globally. Many of the cats in Cyprus are undergoing mass drug administration. Such situations are another place that current diagnostic tests fail to track, in this case for community spread as well as for potential AVR.
Our new project aims to test, track and trace feline coronavirus infections in cats, both at the individual and population level. Our FIP research and current sequencing technology will be mobilized to develop rapid and affordable tests for discriminating between the different coronaviruses linked to FIP-like diseases in the community, as a well as to manage cats with FIP during their course or treatment. We are looking to the future, where clinical care is linked to long term monitoring of cats treated with antivirals, to hopefully shorten the time of treatment as well as to guide the choice of drugs and ensure that any remission of disease is not due to an AVR virus. If present, our tests will guide the owner and clinician to alternative drugs or combination therapy to combat the resistance problem.
Current diagnostics tests are not amenable to the present reality of feline coronaviruses and FIP, and need improving—and the Whittaker lab is ideally positioned to make a difference.
While the long-term goal of the lab remains the prediction of specific FIP mutations in individual cats, such precision medicine approaches can be adjusted for the shorter-term goals of testing, tracking and tracing feline coronaviruses at the community level, and more effectively managing the new life-saving FIP drugs that are now in widespread use.
Position Statement (2020)
We have received many inquiries regarding the use of the GS-441524 in the treatment of FIP. The following is a summary of GS-441524 as well as our position on its current use. Research into the use of this compound was first published by Dr. Niels Pedersen of UC Davis in 2018. Dr. Pedersen’s team published a follow-up study documenting the use of GS-441524 in naturally occurring FIP cases in 2019. The results of both studies were unprecedented with a 100% (10/10) recovery rate reported in experimentally infected cats and 84% (25/31) recovery rate in naturally infected cats. Of the recovered cats, owners reported that they returned to “near normal” within two weeks of treatment. Fever typically resolved within the first 12-36 hours, accompanied by a return in appetite. Effusions resolved over the course of 10-14 days and jaundice gradually receded over the course of 2-4 weeks. The conclusion of the 2019 study proposed the optimized treatment protocol for GS-441624 use as 4.0 mg/kg given as a subcutaneous injection once daily for at least 12 weeks.
Although natural infection proved more challenging to control than experimental infection, a majority of cats in the study responded to treatment. Dr. Pederson is a pioneer in the field of FIP research and there is no question about the legitimacy of his work. Unfortunately, there are many questions surrounding the current use of GS-441524. Most of these concerns relate directly to the fact that this drug cannot be purchased legally from a regulated source. While this has hampered consumer access, it has also blocked research into the best practices for use, and marginalized the role of veterinarians in treatment decisions.
GS-441524 is owned by Gilead Sciences, an American biopharmaceutical company focused on the development of antiviral drugs. Gilead provided GS-441624 to Dr. Pederson for use in his 2018 and 2019 studies, but declined to market the drug for use in cats due to its close relationship to another promising antiviral, remdesivir. Prior to the SARS-CoV-2 pandemic, remdesivir was being tested as a treatment for Ebola. In a story complicated by the challenges of licensing human drugs, it is speculated that Gilead had concerns that any adverse effects from GS-441524 reported in cats would hurt remdesivir in its FDA approval process declined to license it for use in cats.
This created a black-market for GS-441524 led by overseas entrepreneurs looking to capitalize on the desperation caused by a diagnosis of FIP. The treatment course is expensive, ranging anywhere from 1000, to upwards of 10,000 dollars. There is no formal regulation of these black market suppliers or their products. Veterinary professionals may be in legal jeopardy for recommending, dispensing, or administering such unapproved drugs. This combination of factors may prevent cats under treatment from receiving optimal care. We understand that FIP is an otherwise fatal disease so these risks may seem worthwhile, but we caution that the unregulated use of GS-441524 has the potential to promote antiviral resistance and compromise the success of future FIP treatments.
GS-441524 is a nucleoside analog. When the viral RNA polymerase incorporates GS-441524 into the viral genome this jams up the replication machinery and causes premature termination of transcription, hampering the ability of the virus to replicate. We know from experience with nucleoside analogs designed to target HIV that these drugs do not completely suppress viral replication. Use of single-agent therapy leads to the development of resistant strains. Our most successful experience with antiviral treatments involve combination therapies targeting different aspects of viral replication. Such combination treatments lead to superior viral suppression and decrease the incidence of antiviral resistance.
An oral nucleoside analog of GS-441524 is currently being marketed under the guise of a supplement to support the feline immune response. A preliminary study by Dr. Dianne Addie, reports that this treatment stops shedding of the parent enteric coronavirus, also known as FECV. This work investigates the prophylactic use of a nucleoside analog in multi-cat environments where cats are at high risk of developing FIP. While these results appear positive on face value, they raise deep concern for the development of antiviral resistance. While there is a precedent for pre-exposure prophylaxis in people at high risk of contracting HIV, it is important to point out that this medication, known as Truvada, is a combination antiviral therapy. Decades of experience with HIV has demonstrated that monotherapies are much more likely to result in antiviral resistant strains.
Dr. Addie makes a compelling argument for the involvement of veterinarians and researchers in the use of novel FIP therapies. We want to add that there is an obligation to discourage any use that is expected to lead to the development of antiviral resistance. From a one-health perspective, both wild and domesticated cats appear to be susceptible to SARS-CoV-2. This has implications for both the veterinary and human worlds: coronaviruses are well known for their ability to recombine within susceptible hosts and the possibility exists that we will find ourselves in uncharted territory with emergence of recombinant viruses generated under selective antiviral pressure.
One silver lining to the dark cloud of the SARS-CoV-2 pandemic is that we may soon be able to put concerns about the black market use of GS-441524 aside. Its close relative, remdesivir, has recently received FDA approval for use in pandemic SARS-CoV-2 infection in humans. Now that the primary obstacle to licensing has been cleared, we are optimistic that this will pave the way for legal and science-based use of GS-441524 in cats. While the initial studies of GS-441624 showed great promise, important research remains to be done in the setting of broader use. Early data on the efficacy of remdesivir for treatment of COVID-19 illustrated better outcomes than those seen in a larger WHO study, where the drug has at best a modest effect on outcomes.
In regards to combination therapy, there are other potential antiviral drugs in consideration for use against FIP, in particular the protease inhibitor GC376 has an entirely different mechanism of action and is a promising component of combination therapy. (Although not discussed here, use black market GC376 involves a situation very similar to that of GS-441524.) Research into treatment of COVID-19 in humans will undoubtedly lead to the development of therapies that also show promise in cats. Dr. Pedersen has published preliminary data on 25 such compounds, some of which showed potential for combination therapy. While waiting on approval for GS-441524, there will be questions about the off label use remdesivir in cats. We caution that the effects of drugs across species can be unpredictable and laboratory work is needed to determine parameters for safety and efficacy.
For those families living with a diagnosis of FIP and for the veterinarians involved in their care, we understand that the decision to pursue the use of a unlicensed therapy for what is otherwise an invariable fatal disease presents an ethical dilemma. We hope that this statement provides a useful frame of reference on the history of GS-441524 while highlighting the potential for antiviral resistance with unregulated use. Dr. Pedersen has published his own commentary on the unlicensed at home use of FIP antivirals which provides more detailed information on strategies for current use. In the Whittaker Lab, we continue to perform vital basic research into the mechanisms coronaviruses use to expand their cellular tropism with the goal of better understanding the factors that lead to emergence of diseases such as FIP and COVID-19. We are committed to working together in solidarity with our fellow researchers, veterinarians, and cat caretakers to create a future without FIP.