KNOWLEDGE SUMMARY

Keywords: CATS; FELINE IMMUNODEFICIENCY VIRUS; FIV; RETROVIRUS; INTERFERON-OMEGA; rFeIFN-ω; VIRBAGEN® OMEGA; THERAPY

The efficacy of recombinant feline interferon-omega in treating symptomatic cats infected with feline immunodeficiency virus

Rachel Garrett, Student^1*

¹ Sydney School of Veterinary Science, The University of Sydney, Head Office JD Stewart Building University of Sydney, NSW, 2006, Australia
* Corresponding author email: rachel.c.garrett@gmail.com

Vol 8, Issue 3 (2023)
Submitted 18 Feb 2023; published: 15 Sep 2023; next review: 08 May 2025

DOI: https://doi.org/10.18849/ve.v8i3.666

PICO question

In symptomatic cats with feline immunodeficiency virus (FIV), does high-dose subcutaneous recombinant feline interferon-omega (rFeIFN-ω) administration lead to reduced clinical signs compared to cats who were not administered rFeIFN-ω?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Three studies were critically reviewed, including one randomised controlled trial, one non-randomised controlled trial, and one uncontrolled clinical trial.

Strength of evidence

Weak.

Outcomes reported

Each of the studies reported that rFeIFN-ω administration significantly reduced clinical signs in FIV infected cats. However, all three papers have limitations in their study design and statistical analysis which lower the strength of the evidence they provide.

Conclusion

There is only weak evidence demonstrating that rFeIFN-ω administration leads to reduced clinical signs in FIV positive cats. Currently, there is a lack of well-designed, double-blinded, randomised, placebo-controlled clinical trials which have an adequate sample size and specifically focus on FIV positive cats. As a result, more robust evidence is needed to prove the definitive therapeutic benefit of rFeIFN-ω in symptomatic FIV patients. Treatment with rFeIFN-ω may still be considered by clinicians for cats with clinical signs potentially associated with retroviral infection, such as oral lesions and stomatitis, particularly if they are not responding well to supportive therapy alone.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

An 11-year-old, male domestic short-haired cat is presented to you with gingivostomatitis and weight loss. Due to his history of getting into frequent cat fights, you run a point-of-care feline immunodeficiency virus (FIV) / feline leukaemia virus (FeLV) test, and it returns an antibody positive result for FIV. You advise the owner that their cat would benefit from lifestyle changes and supportive therapy, such as dental assessment and cleaning. However, the owner asks if there is any medication available to directly target the cat’s FIV infection and better resolve his clinical signs. You have heard of the use of recombinant feline interferon-omega (rFeIFN-ω) for treating cats with retroviral infections, however you are unsure of how efficacious it is for improving clinical signs in symptomatic FIV patients.

The evidence

Three studies relevant to this Knowledge Summary’s PICO question were identified, including a randomised, double-blinded, placebo-controlled trial (de Mari et al., 2004), a non-randomised controlled trial (Doménech et al., 2011), and an uncontrolled clinical trial (Gil et al., 2013). All three papers had consistent findings regarding the efficacy of rFeIFN-ω for the treatment of symptomatic FIV patients, however the strength of the evidence provided by each study differs.

The de Mari et al. (2004) trial has the best study design with the strongest level of evidence, as it is the only randomised controlled trial out of the three papers. However, it is limited by the fact that all of the FIV positive cats in the trial were coinfected with FeLV, which potentially confounds the study results in relation to this PICO question. Furthermore, the Doménech et al. (2011) trial also employed a control group, however it suffers from the fact that it was not randomised, blinded, or placebo-controlled. Out of the three papers, the final trial by Gil et al. (2013) has the weakest study design due to its lack of a control group, making the study results more prone to bias. Regardless of the study design, all of the papers had a small sample size of FIV positive cats, hence negatively impacting the power of the results in regard to this PICO question.

Summary of the evidence

de Mari et al. (2004)

 

Doménech et al. (2011)

 

Gil et al. (2013)

 

Appraisal, application and reflection

Current treatment of feline immunodeficiency virus (FIV) patients predominantly revolves around supportive therapy, such as controlling secondary infections with antimicrobial drugs (Dunham & Graham, 2008). However, symptomatic FIV patients may benefit from more targeted therapy. One such therapy is recombinant feline interferon-omega (rFeIFN-ω), which has the potential to reduce clinical signs due to its antiviral and immunomodulatory properties (Doménech et al., 2011; and Gerlach et al., 2009). Despite the fact that rFeIFN-ω has been licensed for use in multiple countries for several years, there are limited published in vivo studies which assess how efficacious it is at improving clinical signs in FIV infected cats. This Knowledge Summary aims to critically appraise the existing literature, in order to assist veterinarians in practicing evidence-based medicine when treating symptomatic FIV patients.

A literature search yielded three studies relevant to this PICO question (de Mari et al., 2004; Doménech et al., 2011; and Gil et al., 2013). Each of these studies reported that rFeIFN-ω administration significantly reduced clinical signs in FIV infected cats. However, all three papers had limitations in their study design and statistical analysis which should be considered when interpreting these findings.

None of the papers focused solely on the clinical benefits of rFeIFN-ω in symptomatic FIV positive cats, as all of them also included feline leukaemia virus (FeLV) positive cats in the study population. In both the de Mari et al. (2004) and Doménech et al. (2011) papers, the FeLV and FIV positive cats were not treated as distinct groups when the statistical analysis was conducted. Cats infected with FeLV typically develop more severe clinical signs than those with FIV (Leal & Gil, 2016); therefore, it is possible that including the FeLV cats in the same analysis as the FIV cats skewed the data in these studies, as it could have potentially elevated the average improvement in clinical scores in the treatment group. This issue is compounded by the fact that all of the FIV infected cats in the de Mari et al. (2004) study were also coinfected with FeLV. Based on these factors, it is unknown whether the reported improvement in clinical signs would still be statistically significant in the de Mari et al. (2004) and Doménech et al. (2011) papers if the FIV positive cats were considered separately from FeLV positive cats. Therefore, the specific clinical benefits of rFeIFN-ω treatment in FIV positive cats cannot be ascertained from these studies.

Gil et al. (2013) is the only study that did distinct statistical analysis for the FIV and FeLV positive cats. In this study, it was demonstrated that the FIV positive group specifically had a statistically significant improvement in clinical signs, with 4/7 (57%) cats demonstrating marked improvement. Oral ulcers / gingivitis and caudal stomatitis were the clinical signs that most consistently improved. This is promising data, however rFeIFN-ω can be effective in treating caudal stomatitis even in FIV negative cats (Matsumoto et al., 2018), and therefore the benefits reported by the study may not be applicable to other FIV disease presentations. Additionally, it must be noted that unlike the other two papers, the Gil et al. (2013) study did not include a control group. The study addressed this in its discussion and stated that the clinical scores of the cats at day 0 of treatment could act as the control for each cat. However, the perceived clinical improvement in the cats between day 0 and day 65 could be due to a variety of external confounding factors, such as the level of supportive care received by each cat throughout the study. Thus, without a control it is impossible to prove direct causation between the rFeIFN-ω treatment and the clinical improvement observed.

Conversely, both de Mari et al. (2004) and Doménech et al. (2011) included a control group in their studies. However, the study design of the Doménech et al. (2011) paper had its own shortcomings, as the treatment and control groups were not treated equally throughout the study. The trial was not randomised, and no statistical analysis was conducted at the beginning of the study to ensure the initial clinical scores were similar in the treatment versus the control cats. This introduces selection bias into the study, since it is unknown whether the two groups were equivalent at the beginning of the trial. Given there was a very wide range of initial clinical scores in the study cats, ranging from 0 (asymptomatic) to 6 and above (severe disease), this selection bias could have significantly influenced the perceived clinical improvement in the treatment group compared to the control. Moreover, the study personnel were not blinded. This leads to information bias, particularly since the clinical scoring method utilised in the study was largely subjective and dependent on the opinion of the assessor. The control group cats were also not provided with a placebo, and unlike the treatment group they were housed in a cattery. Since they experienced a different environment from the treatment group throughout the duration of the study, it is possible external factors could have confounded the results, as management and housing conditions can impact FIV disease progression (Beczkowski et al., 2015). Thus, the Doménech et al. (2011) study did not take steps to adequately minimise bias, resulting in a reduction in its internal validity.

Out of the three studies, the de Mari et al. (2004) paper is the only one which is randomised, placebo-control and double-blinded, and thus it represents a stronger level of evidence than both the Doménech et al. (2011) and Gil et al. (2013) studies. However, as mentioned previously, the study population did not contain any cats that were solely infected with FIV, as all the cats were either FeLV infected or FeLV/FIV coinfected. Thus, the population of this study is the least relevant to this Knowledge Summary, and the clinical benefits of rFeIFN-ω demonstrated in the results cannot be extrapolated to FIV patients in practice unless they are also coinfected with FeLV.

Regardless of the study design, no papers provided sample size calculations, and all three studies suffered from a small sample size of FIV positive cats. The de Mari et al. (2004), Doménech et al. (2011) and Gil et al. (2013) studies only included 24, 12, and 10 FIV infected or FIV / FeLV coinfected cats, respectively. This negatively impacts the power of the study results in regards to this PICO question, hence leading to higher rates of random error and poor precision. Hence, veterinarians contemplating the use of rFeIFN-ω should consider that clinical improvement has yet to be reported in a study with a sufficiently large number of FIV positive cats enrolled.

Furthermore, all of the papers failed to consider whether the clinical signs experienced by each cat at the beginning of the study were truly due to FIV. The causative relationship between FIV and clinical disease is not well-established in the majority of circumstances, particularly for non-specific signs such as weight loss (White et al., 2011). Even for more specific clinical signs typically associated with FIV, for example oral lesions and stomatitis, it is still unclear whether FIV plays a major role in precipitating disease (White et al., 2011). Therefore, it is difficult to determine whether the clinical signs evaluated in each study were directly related to FIV infection, or whether they were due to age or other disease processes. As a result, the treatment efficacy of rFeIFN-ω for FIV is hard to accurately assess in these studies, and the inherent complexity of FIV disease associations should be considered when interpreting the results.

The cost of treatment and difficulty of administering subcutaneous injections in some cats may also be limiting factors for clinicians considering the use of rFeIFN-ω. An alternative option is oral administration, an off-label protocol which may be advantageous due to its ease of administration and cheaper cost when compared to the licensed subcutaneous protocol. A 2014 study by Gil et al. evaluated clinical improvement in symptomatic FIV positive cats who received the oral rFeIFN-ω protocol and used the results from the Gil et al. 2013 study on subcutaneous administration as the control group. No significant difference in clinical improvement was observed between the oral and subcutaneous routes of administration, and thus the oral off-label protocol may be a favourable treatment option in some circumstances (Gil et al., 2014). However, the 2014 Gil et al. study suffers from similar issues as the 2013 Gil et al. study evaluated in this Knowledge Summary, namely the lack of a placebo control, as well as a small sample size of only 11 FIV positive cats. Therefore, further critical appraisal of the evidence surrounding the oral protocol is required by clinicians who are considering this route of administration.

In conclusion, due to the limitations outlined above, there is only weak evidence demonstrating that rFeIFN-ω administration leads to reduced clinical signs in FIV positive cats. Although each paper reported that rFeIFN-ω significantly reduced clinical signs, more robust evidence is still needed to prove its definitive therapeutic benefit in symptomatic cats with FIV. Currently, there is a lack of well-designed, double-blinded, randomised, placebo-controlled clinical trials which have an adequate sample size and specifically focus on FIV positive cats; these factors should be considered as essential criteria for those undertaking future studies on the topic. Treatment with rFeIFN-ω may still be considered by clinicians for cats with clinical signs potentially associated with retroviral infection, particularly if they are not responding well to supportive therapy alone.

Methodology

Search strategy

 

Exclusion / inclusion criteria

 

Search outcome

 

ORCiD

Rachel Garrett: https://orcid.org/0000-0002-0939-7329

Conflict of interest

The author declares no conflicts of interest.

References

1. Beczkowski, P.M., Litster, A., Lin, T.L., Mellor, D.J., Willett, B.J. & Hosie, M.J. (2015). Contrasting clinical outcomes in two cohorts of cats naturally infected with feline immunodeficiency virus (FIV). Veterinary Microbiology. 176(1–2), 50–60. DOI: https://doi.org/10.1016/j.vetmic.2014.12.023
2. de Mari, K., Maynard, L., Sanquer, A., Lebreux, B. & Eun, H. (2004). Therapeutic Effects of Recombinant Feline Interferon-co on Feline Leukemia Virus (FeLV)-Infected and FeLV/Feline Immunodeficiency Virus (FIV)-Coinfected Symptomatic Cats. Journal of Veterinary Internal Medicine. 18(4), 477–482. DOI: https://doi.org/10.1111/j.1939-1676.2004.tb02570.x
3. Doménech, A., Miró, G., Collado, V.M., Ballesteros, N., Sanjosé, L., Escolar, E., Martin, S. & Gomez-Lucia, E. (2011). Use of recombinant interferon omega in feline retrovirosis: From theory to practice. Veterinary Immunology and Immunopathology. 143(3–4), 301–306. DOI: https://doi.org/10.1016/j.vetimm.2011.06.008
4. Dunham, S.P. & Graham, E. (2008). Retroviral Infections of Small Animals. Veterinary Clinics of North America: Small Animal Practice. 38(4), 879–901. DOI: https://doi.org/10.1016/j.cvsm.2008.03.005
5. Gerlach, N., Gibbert, K., Alter, C., Nair, S., Zelinskyy, G., James, C.M. & Dittmer, U. (2009). Anti-retroviral effects of type I IFN subtypes in vivo. European Journal of Immunology. 39(1), 136–46. DOI: https://doi.org/10.1002/eji.200838311
6. Gil, S., Leal, R.O., Duarte, A., McGahie, D., Sepúlveda, N., Siborro, I., Cravo, J., Cartaxeiro, C. & Tavares, L.M. (2013). Relevance of feline interferon omega for clinical improvement and reduction of concurrent viral excretion in retrovirus infected cats from a rescue shelter. Research in Veterinary Science. 94(3), 753–763. DOI: https://doi.org/10.1016/j.rvsc.2012.09.025
7. Gil, S., Leal, R.O., McGahie, D., Sepúlveda, N., Duarte, A., Niza, M.M.R.E. & Tavares, L. (2014). Oral Recombinant Feline Interferon-Omega as an alternative immune modulation therapy in FIV positive cats: Clinical and laboratory evaluation. Research in Veterinary Science. 96(1), 79–85. DOI: https://doi.org/10.1016/j.rvsc.2013.11.007
8. Leal, R.O. & Gil, S. (2016). The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives. Veterinary Sciences. 3(4), 32. DOI: https://doi.org/10.3390/vetsci3040032
9. Matsumoto, H., Teshima, T., Iizuka, Y., Sakusabe, A., Takahashi, D., Amimoto, A. & Koyama, H. (2018). Evaluation of the efficacy of the subcutaneous low recombinant feline interferon-omega administration protocol for feline chronic gingivitis-stomatitis in feline calicivirus-positive cats. Research in Veterinary Science. 121, 53–58. DOI: https://doi.org/10.1016/j.rvsc.2018.10.003
10. White, J., Stickney, A. & Norris, J.M. (2011). Feline Immunodeficiency Virus: Disease Association Versus Causation in Domestic and Nondomestic Felids. Veterinary Clinics of North America: Small Animal Practice. 41(6), 1197–1208. DOI: https://doi.org/10.1016/j.cvsm.2011.07.003

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