Effect of telephone reminders on adherence to anti-rabies vaccine amongst animal bite patients in North India: A randomised, single-blind, parallel-group, single-centre, interventional superiority trial

Highlights

• •Enhanced compliance through telephone reminders: implementation of telephone reminders before each dose significantly enhances patient adherence.
• •Adherence improvement: the intervention group exhibited a 16.5% higher adherence rate compared with the non-intervention group.
• •Demographic factors and adherence: age and gender did not significantly impact adherence, reinforcing the intervention's effectiveness.
• •Cost-effective digital intervention: this straightforward and inexpensive intervention, pertinent in the digital era, provides a viable model framework for other countries.

Abstract

Objectives

Rabies is a highly infectious viral zoonotic disease of the central nervous system with a near 100% fatality rate. Vaccine adherence is an integral part of achieving effective treatment. India accounts for 27% of the global deaths from rabies yearly. Rabid dog bites are responsible for 99% of these deaths. This study aimed to assess the effect of reminder calls on compliance with the anti-rabies vaccine among animal bite patients.

Methods

An interventional, randomised, single-blinded, parallel-group, single-centre study was conducted at the Anti Rabies Clinic, Rajindra Hospital, Government Medical College, Patiala, a city located in Punjab, India, with a population of approximately 19 lakhs. A sample of 400 patients was enrolled and divided into two groups by lottery method. After obtaining written and informed consent from patients, data were collected using a validated pre-tested, semi-structured proforma. The intervention group received reminder calls before each dose. At the end of the study, complete information regarding compliance was obtained from both groups and analysed.

Results

The median age group of the animal bite patients was 21-40 years, with most being male (69.50%). Most of the bites were on the lower extremities (64.0%), followed by the upper extremities (29.0%) and the face (3.25%). Out of 153 patients who delayed the dose, 137 (89.54%) delayed a single dose. The 4th dose on the 28th day was the most frequently delayed dose (75.16%). Reminder calls increased the vaccine compliance rate from 53.5% in the non-intervention group to 70% in the intervention group (adjusted odds ratio=2.28; P=0.0002). There was no effect of gender, area, educational qualification, or marital status on the compliance.

Conclusions

Reminder calls were found to have significant effect on the adherence to the anti-rabies vaccine. This simple, cost-effective, and patient-friendly intervention must be integrated within the health care system to ensure timely and complete administration of the anti-rabies vaccine to reduce the risk of rabies.

Introduction

Rabies is a neglected zoonotic tropical disease that usually affects the poorest communities. It is the world's deadliest disease, which has a 100% fatality rate and, at the same time, is 100% preventable [1]. Globally, approximately 59,000 human deaths are attributed to dog-mediated rabies annually, i.e., approximately one person dies of rabies every 9 minutes, with a loss of 3.7 million disability-adjusted life years (DALYs). Asia accounts for 59.65% (35,172) of rabies-associated deaths, which renders a loss of 2.2 million DALYs [2]. In India, one person is bitten by an animal every 2 seconds, and one person dies of rabies every 30 minutes [3]. India accounts for 27% of the global deaths from rabies yearly. Rabid dog bites are responsible for 99% of these deaths [4]. The Indian post-exposure prophylaxis (PEP) protocol for rabies involves proper wound categorisation, local administration of anti-rabies immunoglobulin, and anti-rabies vaccine (ARV) on days 0, 3, 7, and 28, which is based on the updated Thai Red Cross regimen adopted by India since 2006. Vaccine compliance is an essential part of achieving effective treatment [5,6].

A recent study found that only 77% of patients completed the entire intra-dermal rabies vaccination course, which needs to be improved [7]. Low patient compliance with the rabies vaccination schedule can be due to the long duration of treatment, high cost, lack of time for visits, and loss of income due to frequent travel [8]. Poor compliance or non-compliance with the prescribed vaccination schedule significantly impacts the mortality rates following animal bites. To accomplish the target of zero deaths due to rabies by 2030, 100% compliance with PEP remains the critical strategy [2]. Text message reminders have been proven to promote effective communication with health care providers, leading to improved compliance with animal bite patients and better health outcomes among patients [9].

Considering this background, this study aimed to determine whether there was a statistically significant difference in treatment adherence between the intervention and non-intervention groups. The secondary outcome was the difference in sociodemographic and other characteristics between the intervention and non-intervention groups.

Methods

We conducted an interventional, randomised, single-blinded, parallel-group, single-centre study. The study was conducted at an anti-rabies clinic situated in the Rajindra Hospital, Government Medical College, Patiala, Punjab in the northern part of India. The study was conducted after due approval from the Institutional Ethics Committee and Clinical Trials Registry - India from 22 November 2023 to 18 January 2024.

For the calculation of sample size for this clinical trial, we used the online sample size calculator ClinCalc. The study design involved two groups, with the primary end point being dichotomous. On the basis of a previous study, we anticipated a prevalence of 77% in one group and 93% in the other. The sample size was calculated assuming a 5% alpha error and an enrolment ratio of 1 in each group. Given the very high incidence of animal bite in our anti-rabies clinic and to increase the precision and reliability of our results, 200 participants were enrolled in each group. The sample size calculation was performed as follows:

N1={z1−α/2∗p¯∗q¯∗(1+1k−−−−−−−−−−−√)+z1−β∗p1∗q1+(p2∗q2k−−−−−−−−−−−−−−√)}2/Δ2q1=1−p1q2=1−p2p¯=p1+kp21+Kq¯=1−p¯N1={1.96∗0.855∗0.145∗(1+11−−−−−−−−−−−−−−−−−√)+0.84∗0.78∗0.22+(0.93∗0.071−−−−−−−−−−−−−−−−−−−−√)}2/0.152N1=85N2=K∗N1=85

• p1, p2=proportion (incidence) of groups #1 and #2

• Δ=|p2-p1|=absolute difference between two proportions

• n1=sample size for group #1

• n2=sample size for group #2

• α=probability of type I error (0.05)

• β=probability of type II error (0.2)

• z=critical Z value for a given α or β

• K=ratio of sample size for group #2 to group #1

A total of 400 patients were enrolled in the study. All patients presenting with recent animal bites to the clinic for the first dose of ARV and willing to continue treatment at this clinic were recruited into the study. Those referred from other centres only for immunoglobulin infiltration and those who intended to finish their ARV course at another centre were excluded from the study1 (Figure 1). A medical attendant filled in the baseline characteristics and all other relevant details on a pre-tested semi-structured questionnaire at the study site. Socioeconomic status of participants was determined using the Modified BG Prasad Scale [10].

Figure 1.

Study design.

All participants provided oral informed consent at the time of the first dose of the ARV after the nature of the study was explained to them by a trained medical attendant (MD faculty doctor permanently assigned to the anti-rabies clinic).

Wounds were categorised as per the World Health Organization criteria [11] as follows:

• •Category 1: touching/nibbling or feeding of animals on intact skin, or contact with the saliva of a rabid animal or person on intact skin. These patients do not require any medical intervention except thorough wound cleaning and were excluded from the study.
• •Category 2: nibbling on uncovered skin, minor scratches, or abrasions without bleeding.
• •Category 3: single/multiple transdermal bites or scratches, licks on broken skin, or contamination of mucous membranes with saliva from licks or bats [11].

We defined the following criteria for compliance after consultations with experts in this field:

• •Adherent: participants who received the scheduled doses of ARV on the recommended dates.
• •Non-adherent: participants who deviated from the scheduled regimen by 1 day or more.

A trained non-participating medical professional (MD faculty doctor) managed participant randomisation at the study site using a precise protocol. Participants’ names were written on individual slips of paper and placed in a randomisation pool, each folded to conceal its contents. Based on the sequence of their selection, participants with even numbers were allocated to the interventional group, while those with odd numbers were assigned to the non-interventional group. On an average day, 13 new patients would attend the clinic, with six placed in the intervention group and seven in the non-intervention group. This process continued until each group reached 200 participants, ensuring a systematic and accurate randomisation procedure.

In the intervention group of the study, each patient received a telephone reminder 1 day before each dose, receiving a total of three calls on day 2, day 6, and day 27. According to the pre-designed protocol, the investigator made a total of three calls in vernacular language to each patient, with three attempts per call. During the first call, patients were advised to save the number as ‘Rajindra Hospital’ to facilitate callbacks in case any future calls were missed. In the current study, only a few participants missed the first call attempt. However, all of them returned the call before the three attempts were exhausted. Each call lasted between 40 and 50 seconds on average, with a maximum duration of 2 minutes.

Every call was answered or the patient called back. The first call was made after 5 pm, and if the patient did not answer, the first re-attempt was made within 5-10 minutes. If this call was unanswered again, the second re-attempt was made at 7 pm. These second re-attempts were needed for a successful contact for 19 patients.

All patients were advised to keep their treatment documentation even after completing the treatment to prevent unnecessary additional treatment in case of re-exposure due to lack of documentation. This advice was given verbally and also noted on the treatment slips of each patient.

Data were collected using a structured proforma that was pre-tested and validated. The data were entered into Microsoft Excel 2019. Descriptive statistics were used to present categorical data as percentages. We applied logistic regression analysis to assess the association of reminder calls and other factors with ARV compliance, using IBM SPSS Statistics, trial version 26.

This study was approved by the Clinical Trials Registry - India (Reg No. CTRI/2023/11/060031, dated 20/11/2023; secondary ID: U1111-1298-3944 under the Universal Trial Number [UTN] system).

Results

During this study, we enrolled 400 patients who had been bitten by animals and were seeking medical attention. Out of these 400 patients, 200 were selected randomly to receive the intervention through reminder calls a day before their 3rd-, 7th-, and 28th-day doses. The remaining 200 patients were included in the non-intervention group.

More than two-thirds (69.50%) of participants were male. The median age group of the patients was 21-40 years (Table 1). Most had a high school education, representing 22.50% of the total, while those with an intermediate diploma represented the smallest group at 4.75%. Most residents resided in urban areas (63.00%), as opposed to 9.00% in peri-urban areas. The sample consisted of 53.25% married individuals, whereas widows constituted only 2.25%. Regarding occupation, the self-employed category was the largest at 32.25%, whereas government employees constituted the smallest category at 2.00%. Socioeconomically, Class 2 had the highest representation at 29.25%, with Class 5 being the lowest at 4.25%.

Table 1.

Patient gender and age distribution.

Variables	Number (n=400)	Percentage (%)	Intervention group	Non-intervention group
Gender
Male	278	69.50	141	137
Female	122	30.50	59	63
Age (years)
0-20	100	25.00	52	48
21-40	182	45.50	94	88
41-60	88	22.00	38	50
>60	30	7.50	16	14

Category 3 bites accounted for 98% of the total bites; 64% of bites were on the lower extremities, 29% on the upper extremities, and 3.25% on the face; 3.75% of patients had bites on other sites or multiple bites. Tetanus toxoid was administered in 66% of cases (Table 2).

Table 2.

Animal bite profile.

Variables	Number (n=400)	Percentage (%)	Intervention group	Non-intervention group
Site (n=400)
Lower limb	256	64.00	126	130
Upper limb	116	29.00	58	58
Face	13	3.25	8	5
Other sites	15	3.75	8	7
Category of bite (n=400)
Category 2	8	2.00	4	4
Category 3	392	98.00	196	196
Tetanus toxoid (n=400)
Yes	264	66.00	121	143
No	136	34.00	79	57

Most bites were unprovoked (81.25%). Treatment was sought within 6-24 hours of being bitten by 46.25% of patients. The wound was washed with soap and water by 53% of patients, while 42% used remedies such as red chili powder and turmeric, with 18% applying them after washing the wound.

Dogs were the most common biting animal (95%), and 31.75% of bites were by pet animals, with 27.56% having a history of biting others (Table 3).

Table 3.

Biting animal details.

Variables	Number	Percentage (%)	Intervention group	Non-intervention group
Biting animal (n=400)
Dog	380	95.00	190	190
Cat	10	2.50	4	6
Othersa	10	2.50	6	4
Type of biting animal (n=400)
Stray	249	62.25	126	123
Adopted strayb	24	6.00	15	9
Pet	127	31.75	59	68
History of biting others (pet dog n=127)
Yes	35	27.56	20	15
No	92	72.44	48	44

^a‘Others’ include three mongooses, five monkeys, one horse, and one rabbit.

^bThose which were fed and taken care of by community members.

Out of 400 bite victims, 200 received telephone reminders before each mentioned dose of ARV; 70% (140) of the intervention group and 53.5% (107) of the non-intervention group adhered to the schedule. On application of logistic regression, we found that the odds of patients adhering to the vaccination schedule were 2.28 times higher in the intervention group than in the non-intervention group (Figure 2; Table 4).

Figure 2.

Difference in compliance between the intervention (reminder calls) and non-intervention group.

Table 4.

Logistic regression analysis of factors affecting compliance.

Groups	P-value	Adjusted odds ratio	95% confidence interval for EXP(B)
			Lower	Upper
Non-intervention group
Intervention group	0.0002	2.28	1.48	3.50
Gender
Female
Male	0.81	1.07	0.63	1.82
Area
Urban
Rural	0.84	0.95	0.57	1.58
Peri-urban	0.98	1.01	0.47	2.17
Marital status
Married
Unmarried	0.77	0.91	0.47	1.74
Widow	0.32	0.46	0.10	2.12
Educational status
Illiterate
Primary school
Middle school
High school
Intermediate/diploma	0.54	0.79	0.37	1.68
Higher education	0.51	0.75	0.32	1.76
Graduate
Post-graduate
Type of animal
Pet
Totally stray	0.02	1.84	1.12	3.02
Adopted stray	0.47	1.43	0.55	3.70

A total of 153 patients were delayed in receiving follow-up doses of ARV; 71.24% of these patients were male, and 63.39% lived in an urban area. Of them, 137 (89.54%) were delayed for a single dose, and 16 (10.46%) were delayed for two doses. The fourth dose on the 28th day was the most frequently delayed dose (75.16%) (Figure 3).

Figure 3.

Number of doses in the anti-rabies vaccine schedule delayed by the study population.

The significant reasons for non-compliance with vaccination schedules as stated by patients are depicted in Figure 4.

Figure 4.

Reasons for non-compliance with the anti-rabies vaccine schedule.

ARC, Anti Rabies Clinic.

Additionally, a correlation was observed in logistic regression between the type of animal that bit an individual and their compliance with the ARV, with those bitten by totally stray animals exhibiting better compliance (adjusted odds ratio, 1.81; P=0.002). However, no correlation was found between gender, area, educational qualification, or marital status and compliance with the ARV in logistic regression analysis (Table 4).

The study was granted ethical approval by the Institutional Ethics Committee of Rajindra Hospital, Government Medical College, Patiala, Punjab (vide letter no. Trg.9[310]2023/35281, dated 23/10/2023).

Discussion

In the present study, the compliance rate among the intervention group was 70%, which differed from an earlier study that reported a compliance rate of 55% [12]. However, our findings aligned with those of another previous study, which reported a 77% compliance rate with the intra-dermal rabies vaccine [13]. In other studies where no reminders were sent, the recorded compliance rates were only 34.3% and 42.81%, respectively [6,14].

This study found a significant association between the intervention and the patients’ compliance with the ARV. Our findings were similar to those of another study that reported an increased likelihood of completing the PEP doses among participants who received short message service reminders compared with those who did not [9]. The intervention of telephone reminders is a two-way communication method and hence builds rapport and motivates patients, in addition to being inexpensive, easy-to-implement, and patient-friendly.

In our study, we observed that the fourth dose was the most commonly delayed dose (75.2%), which is in concordance with a previous study [5]. In another study, it was found that the dropout rate increases with time, implying that the gap of 3 weeks between the third dose and the last dose could be a reason for the dropouts [15]. Vaccine fatigue is a phenomenon wherein individuals become less compliant with vaccination schedules because of the repetitive nature of the appointments. This can lead to delays in receiving the fourth dose, as individuals may feel less urgency or experience inconvenience. The success of completing a vaccination series often depends on effective follow-up and reminders. If there is insufficient reinforcement from health care providers or lack of reminder systems, individuals may be less likely to adhere to the schedule for later doses.

The primary reasons for non-compliance with vaccination schedules included being out of town (34%), forgetting vaccination dates (24.8%), and conflicts with job or school schedules (19.6%). Another study found that lack of time (50%) and the animal's health status (25%) were significant reasons [16]. In a separate study, hospital distance (20%), forgetting dates (18.4%), going to their hometown (15.3%), and inconvenient timings (7.7%) were primary causes of delayed doses [17]. Addressing these issues requires enhanced reminder systems, flexible scheduling, and improved accessibility through mobile clinics to ensure better adherence to treatment protocols.

Most of the bites were reported in the 21-40-year age group (46%), with 88.8% of them being literate, similar to the findings of a previous study [2]. Out of 400 patients, more than two-thirds were male patients (69.5%), consistent with previous studies [[18], [19], [20]]. This could be due to adult males being more involved in outdoor activities, thus increasing their chances of exposure to animal bites.

The lower extremity was the most common bite site (64%), which aligns with prior research, likely because of its easy accessibility to the biting animal [[18], [19], [20]]. Approximately 10.5% of patients used irritants such as surma, red chili, and turmeric powder on the wound [19]. The use of these substances can be attributed to traditional or cultural practices aimed at treating wounds. However, these methods are not recommended by medical professionals, as they can potentially exacerbate the injury and delay proper treatment, increasing the risk of infection and complications. Applying such irritants facilitates the movement of rabies virus upwards via nerve endings rather than killing it.

In this study, 73% of patients sought treatment within 24 hours following a bite, comparable to other studies [18,19]. This could be due to fear associated with the disease and increased awareness about the availability of treatment for animal bites at health care facilities.

Strength and limitations

This study has the unique strength of being one of the few studies that are primarily focused on rabies disease. The study demonstrated that telephone reminders positively influence the adherence of animal bite victims to completing PEP on time. This adherence protects the patients and saves valuable anti-rabies biologicals that are wasted when the patients do not complete their entire course, as per the national guidelines on rabies.

This finding is particularly pertinent for policymakers and health care planners striving for equitable health care interventions. Integrating telephone reminder systems into national rabies prevention programs could be a cost-effective, scalable, and inclusive strategy to move closer to the goal of zero rabies fatalities.

While our study's findings are promising, the single-centre design limits the extrapolation of results to broader populations. Multi-centre trials across varied socioeconomic and cultural landscapes would provide more definitive evidence of the intervention's effectiveness. Further research should also consider the cost–benefit analysis of implementing telephone reminders at scale, considering both direct costs and the potential savings from prevented rabies cases. Additionally, qualitative studies exploring patients’ perceptions of telephone reminders could illuminate the psychological drivers behind enhanced vaccine adherence, offering more profound insights into human-centred design in health care intervention.

Conclusion

Telephone reminders had a positive impact in increasing the adherence with the ARV. The study provides compelling evidence that telephone reminders are a valuable tool in enhancing adherence. This cost-effective and patient-friendly intervention can be widely adopted to ensure better adherence and reduction in mortality amongst animal bite victims. The research also uncovered common barriers to adherence, such as being out of town, forgetting vaccination dates, and conflicts between work schedules and outpatient department hours.

Declarations of competing interest

The authors have no competing interests to declare.