Maximizing adherence to minimize heartworm resistance

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Heartworm disease is a threat to canines and felines in all 50 states. Although the disease can be fatal, preventives are widely available and highly effective.

Resistant strains of heartworm are present in the United States. Protecting patients from infection with resistant strains and minimizing the continued development of resistance requires veterinarians to evaluate current prevention strategies and work to maximize adherence with both prevention and treatment protocols.

Heartworm life cycle

Dirofilaria immitis is the nematode parasite that causes heartworm disease. Microfilaria are ingested by mosquitoes during a blood meal from an infected dog. They undergo several molts into the infective third-stage larvae (L3) within the intermediate host. Within days of entering the host, L3 molt to fourth-stage larvae (L4), which migrate through the host’s body toward the circulatory system. Within 45 to 65 days, the L4 begin their final molt to the juvenile or immature adult stage.

Within 90 to 120 days following infection, all immature adult worms reach the pulmonary vasculature, where they will continue to develop into mature adult worms that will reproduce. Between 6 and 9 months following infection, the dog will develop patent infection with circulating microfilaria, which creates a reservoir for infection.

Heartworm prevention and the role of adherence

The American Heartworm Society (AHS) recommends that dogs receive year-round heartworm prevention regardless of where they reside.¹ All available FDA-approved heartworm prevention products are members of the macrocyclic lactone (ML) drug class. MLs are safe for all breeds, even those with MDR mutations, at prescribed doses.¹ These drugs are highly efficacious against L3 and early L4 stages (< 30 days old).

Most FDA-approved preventive products are available in topical or oral forms for dogs and cats. These products rely on pulse administration of a low dose of ML once every 30 days, which works to kill larval heartworms that have been transmitted to the patient in the preceding month. The drug is eliminated from the body within a few days of administration, making timely dosing essential. Because L4s can molt into the juvenile stage in 45 days and late-stage L4, juvenile, and adult heartworms are less susceptible to MLs, a single missed dose of these preventive may result in infection.¹

Adherence is the largest barrier to effective heartworm prevention. When evaluating adherence with monthly preventive products, several factors need to be evaluated. These include the following:

• Were the appropriate number of doses purchased by the client for a given period?
• Was the product purchased/administered appropriate for the weight of the patient at the time of administration?
• Was the product administered at appropriate intervals?
• For oral products, did the patient ingest the full dose?
• For topical products, was it applied to the skin in an effective manner?

Many of these factors are difficult to evaluate on a wide-scale basis to assess adherence, but several studies have evaluated purchase adherence. Data show that approximately two-thirds of US dogs do not receive any heartworm prevention.² On average, only 8.6 doses are purchased per patient annually, falling short of the recommended 12 doses per year.² In a study evaluating lack of efficacy claims, where a patient said to be on heartworm prevention tested antigen positive, 80.7% of cases were found to have insufficient heartworm prevention purchased.³

An alternative prevention strategy for dogs is the use of injectable products administered in the veterinary clinic. Two long-acting injectable products are available, providing protection for either 6 or 12 months with a single injection. These products rely on the continuous release of moxidectin to eliminate larval heartworms. Purchase adherence with injectable heartworm preventives has been found to be superior to monthly products.⁴ Additionally, administration of the product in the veterinary office removes concerns that the patient was dosed appropriately.

Identifying ML resistance in the clinic

Suspicion of heartworm resistance to MLs has been reported for over 20 years and has more recently been confirmed in the United States.⁵ Resistant strains appear to be most prevalent in states along the lower half of the Mississippi River.⁵ The full distribution of these strains has yet to be evaluated and ongoing research is needed to further identify resistance.⁵

Identification of ML-resistant D immitis is difficult and requires experimentally infecting a naïve dog with a suspected resistant strain following administration of an ML and monitoring for development of infection.^5,6 Genetic analysis of resistant strains is ongoing to better understand mechanisms of resistance.^1,5 Despite the identification of single nucleotide polymorphisms (SNPs) in some strains of ML-resistant D immitis, genotyping is not practical to use in the clinic to identify cases of resistant disease.⁵

When a patient on preventives develops a heartworm infection, resistance should not be immediately assumed. Adherence in purchasing and administering appropriate preventives should be evaluated closely. An algorithm that can be used in the clinic to investigate potential resistance was developed by investigators.⁶ The algorithm relies on use of a microfilarial suppression test. A reduction in microfilaria by more than 90% indicates that resistance is unlikely.⁷

Combating resistance

Although resistant strains exist, it is important to note that in most cases, MLs are still reliable preventives.⁷Combating resistance will require maximizing the dosage and formulation of available MLs into highly effective preventives as well as maximizing adherence in administering existing preventives.

Variability in the efficacy of MLs exists and is related to the inherent properties of each drug. For instance, moxidectin is more lipophilic, has a higher potency, and has a longer half-life than other MLs.^8,9 Recent literature has demonstrated that moxidectin has higher efficacy than other MLs against resistant strains of D immitis, especially in sustained-release, pet parent-administered products.⁹ Thus, especially in areas with higher concerns for resistance, moxidectin-containing products may offer superior protection.

In practice, veterinarians can combat resistance by educating clients on the importance of year-round prevention, annual testing, and appropriate treatment for infected dogs. Recommendations for combating resistance in practice include the following:

• Begin heartworm prevention in puppies by 8 weeks of age and continue year-round.¹
• Consider the use of long-acting injectable preventives to improve adherence.⁵ An added advantage of these products is that all available injectable preventives for D immitis contain moxidectin.
• Include mosquito repellent products and environmental control of mosquitoes in your prevention strategy, especially in endemic areas, to minimize transmission.^1,5
• Doxycycline can be administered to patients with resistant D immitis strains to help minimize transmission.⁵ At 10 mg/kg twice daily, doxycycline kills the symbiotic bacteria Wolbachia pipientis. In the absence of W pipientis, D immitis is unable to produce viable microfilaria. Additionally, microfilaria exposed to doxycycline are unable to develop into infective larval stages when ingested by mosquitos.
• Follow AHS guidelines for adulticidal therapy using melarsomine. The use of “slow-kill” methods for heartworm disease that rely on MLs is not recommended. Prolonged use of MLs in adult worms may select for resistant subpopulations and create a reservoir for resistant infection.¹

Take-home message

Macrocyclic lactone drug resistance has been observed in some strains of D immitis, but the mechanisms of resistance, prevalence of resistant strains, and their distribution are still being investigated. As all available FDA-approved heartworm preventives rely on MLs, it is imperative that veterinarians work with clients to combat resistance through improving adherence in preventive administration and follow AHS guidelines when presented with a heartworm-positive patient.

Kate Boatright, VMD is a 2013 graduate of the University of Pennsylvania School of Veterinary Medicine, is a practicing veterinarian and freelance speaker. She is passionate about mentorship, education, and addressing common sources of stress for veterinary teams and recent graduates. Outside clinical practice, Boatright is actively involved in organized veterinary medicine at the local, state, and national levels.

References

1. American Heartworm Society. Current canine guidelines for prevention, diagnosis, and management of heartworm infection in dogs. Revised 2018. Accessed April 16, 2022. https://www.heartwormsociety.org/veterinary-resources/american-heartworm-society-guidelines
2. Drake J, Wiseman S. Increasing incidence of Dirofilaria immitis in dogs in USA with focus on the southeast region 2013-2016. Parasit Vectors2018;11(1):39. doi:10.1186/s13071-018-2631-0
3. Atkins CE, Murray MJ, Olavessen LJ, Burton KW, Marshall JW, and Brooks CC. Heartworm ‘lack of effectiveness’ claims in the Mississippi delta: computerized analysis of owner compliance. Vet Parasitol. 2014;206(1-2):106-113. doi:10.1016/j.vetpar.2014.08.013
4. Mwacalimba K, Amodie D, Swisher L, et al. Pharmacoeconomic analysis of heartworm preventive compliance and revenue in veterinary practices in the United States. Front Vet Sci. 2021;8:602622. https://doi.org/10.3389/fvets.2021.602622.
5. Prichard RK. Macrocyclic lactone resistance in Dirofilaria immitis: risks for prevention of heartworm disease. Int J Parasitol. 2021;51(13-14):1121-1132. doi:10.1016/j.ijpara.2021.08.006
6. Moorhead AR, Evans CC, Kaplan RM. A diagnostic algorithm for evaluating cases of potential macrocyclic lactone-resistant heartworm. Parasit Vectors 2017;10(suppl 2):109-113. doi:10.1186/s13071-017-2441-9
7. American Heartworm Society. Resistance statement. Accessed April 17, 2022. https://www.heartwormsociety.org/images/Resistance_Statement_20200716.pdf
8. Prichard RK and Geary TG. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelminthic resistance. Int J Parasitol Drugs Drug Resist. 2019;10:69-83. doi:10.1016/j.ijpddr.2019.06.002
9. Savadelis MD, McTier ML, Kryda K, Maeder SJ, Woods DJ. Moxidectin: heartworm disease prevention in dogs in the face of emerging macrocyclic lactone resistance. Parasit Vectors 2022;15(1):82. doi:10.1186/s13071-021-05104-7