of oral and written information. Four criteria of compliance were applied to travelers: 3 capsules needed to be swallowed. (criterion 1) on day 1, 3 and 5 (criterion ...
Compliance to Live Oral Ty21a Typhoid Vaccine, and its Effect on Viability Claire-Lise Fallab Stubi, Pierre R. Landry, Christine Pétignat, Jacques Bille, Blaise Genton, Roger Darioli, and Michel Burnier Background: Concerns have been expressed that in travelers the efficacy of the live oral Ty21a typhoid vaccine Vivotif® could be lower than reported, maybe due to a lack of compliance. The purpose of this study was to examine the level of compliance with the recommendations regarding dosing, timing of dosing with respect to food intake, and storage. Method:Travelers were randomized into two groups: one received oral information only, and the second, a combination of oral and written information. Four criteria of compliance were applied to travelers: 3 capsules needed to be swallowed (criterion 1) on day 1, 3 and 5 (criterion 2), at least 1 hour before or 2 hours after a meal (criterion 3) and the vaccine had to be kept refrigerated (2–8°C) (criterion 4). Compliance was evaluated using three different methods: a questionnaire, pill counting, and electronic monitoring using the Medication Event Monitoring System (MEMS®). Storage conditions were checked by temperature tags, and viability of the vaccine was assessed by culturing the content of remaining capsules. Results:The data of 115 travelers were analyzed. All the travelers took the 3 capsules. Compliance to all four criteria was complete in 68% of travelers according to the questionnaire, and 53% according to the MEMS (p = .05). Sixty-seven percent of all the doses intervals were of 48 hours 6 hours, 12% being shorter than 36 hours and 7% longer than 60 hours. Eighty-seven travelers (76%) took their capsules on each alternate day. The method of information had no significant impact on compliance. Forty-two percent of tags showed exposure to temperature over 10°C for more than 24 hours. Yet, no difference could be found in the viability of the vaccine compared with controls. Conclusions: Most travelers take their 3 capsules on alternate days, but many did not follow the other recommendations. Electronic monitoring of compliance provides more accurate results than questionnaires. Emphasis must be put on motivating the travelers to take the vaccine as recommended.
Typhoid fever is a serious febrile disease due to a gram-negative enterobacterium, Salmonella typhi, acquired by ingestion of contaminated food or water. Typhoid fever is endemic in developing countries but most cases in Europe and in the United States are imported. Between 1989 and 1997, 20 to 50 cases have been reported annually in Switzerland,1,2 and most of the cases got infected abroad, mainly in Asia. The global risk for travelers has been estimated at 1: 30,000, but higher incidences have
been reported in high risk groups or in high risk destinations.3 Therefore an efficient and well tolerated vaccine would be welcomed to complete the prophylactic measures recommended to travelers at risk. Two vaccines have been developed in the last decade, an injectable polysaccharide capsular vaccine made of Vi antigen from S. typhi (Typhim-Vi®, Pasteur Merieux) showing a protective efficacy of 75 to 81%,4,5 and a live attenuated oral vaccine made of a mutated Salmonella typhi (Ty21a strain) (Vivotif ®, Berna) showing a protective efficacy of 50 to 96%.6–9 In Switzerland, this last vaccine is given orally in three doses, as one gastroresistant capsule every other day, and should be kept between 2° and 8° Celsius. Protection under constant exposure lasts 3 years, but only 1 year in nonendemic conditions. All the studies of efficacy have been conducted in populations of endemic areas, but not in travelers.6–9 There has been concern that the efficacy in travelers could be much lower than reported.10 Causes incriminated have been a lack of antigenicity, whether by absence of natural exposure to the bacteria or by a too low content in S. typhi, or non observance of the recommendations for use.10–12 Indeed, following the multiple recommendations for taking the vaccine requires a high level of compliance, and compliance is known to be poor when instructions for use are complicated or numerous. 13 All the studies of
Claire-Lise Fallab Stubi, Pierre R. Landry, MD, DTMH, Blaise Genton, MD, PhD, Roger Darioli, and MD, Michel Burnier, MD: University Medical Policlinic, Lausanne, Switzerland; Christine Pétignat, MD, and Jacques Bille, Professor: Institute of Microbiology, University Hospital, Lausanne, Switzerland. These results were presented orally at the Fourth International Conference on Travel Medicine, April 23–27, 1995, Acapulco, Mexico. The vaccines used in this study and partial financial support were given by Berna (Vivotif®), Bern, Switzerland. Reprint requests: C-L. Fallab Stubi, Policlinique Médicale Universitaire, Rue César Roux 19, 1005 Lausanne, Switzerland. J Travel Med 2000; 7:133–137.
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compliance in the use of Vivotif ® Berna vaccine have been done by questionnaires with results showing that dosing at the appropriate interval, and refrigeration issues, to be the most common compliance errors.11,14,15 Assessing compliance by this method is limited by the subjectivity of the participants. In general, self reporting questionnaires asking the patient about his own compliance overestimate true compliance.16 New methods of compliance assessment include electronic monitoring,17,18 which takes off the subjectivity linked to questionnaire assessment by precisely timing the openings of the vial containing the drug or vaccine under evaluation. Comparisons between electronic monitoring of drug compliance, and pill count or urine tests, have repeatedly demonstrated that both the pill count and the urine tests overestimate drug compliance.19–22 Thus, electronic monitoring is considered today, the most reliable approach to monitor compliance to drug therapy. It has been used extensively to monitor or sustain adherence to drug regimen in several diseases including epilepsy, tuberculosis, and hypertension.20,22,23 This study aimed at measuring compliance of travelers in taking the oral typhoid vaccine Vivotif® as recommended after oral, or oral plus written explanations, with the use of an electronic monitoring device, with the pill count, and with a questionnaire. The impact of nonobservance of the requirements for storage on the viability of S. typhi contained in the vaccine was assessed as well. Subjects and Methods
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approved by the local ethical committee. A preliminary questionnaire recorded personal data, data on the planned journey, the health of the travelers, and on concomitant drugs being taken. On the same day as they entered the study, the travelers received other necessary vaccines and recommendations on malaria prophylactics, as well as preventive measures against diarrhea. Intervention
Travelers were allocated into two groups by simple random procedure (pre-prepared envelop): one group received oral information about the use of the vaccine, and the other received oral and written information (a card provided by the manufacturers). All travelers received a questionnaire asking about date and time of meals, time of use of medication, side effects, place of storage, and a MEMS® (Medication Event Monitoring System, APREX Corporation, Palo Alto, CA) consisting of a bottle, closed with a cap containing a microprocessor recording the date and the time of all openings. This system assumes that each bottle opening corresponds to a dose taken. They were made aware of the MEMS recording process and the bottle was filled with 6 capsules of vaccine and 2 time/temperature tags (Monitor Mark 3M), one recording any temperature over 10°C, and the other one any temperature over 30°C. The travelers had to take the bottle home, keep it in their refrigerator, take the capsules of vaccine as recommended, fill in the questionnaire, and bring the bottle with the tags and the remaining capsules back as soon as possible after taking the last dose.
Vaccine and Recommendations for Use
The Vivotif ® vaccine, produced by Berna, Switzerland, contains 109 units of attenuated Salmonella typhi (Ty21a strain) per capsule. To ensure an effective vaccination four criteria must be fulfilled: 3 capsules need to be swallowed (criterion 1) on day 1, 3 and 5 (criterion 2), at least 1 hour before or 2 hours after a meal (criterion 3), and the vaccine must be kept refrigerated (2–8°C) (criterion 4).
Compliance Assessment
Subjects
Viability Assessment
All successive willing travelers over 18-years-old visiting our travel clinic prior to a trip to high risk areas were asked to participate. High risk areas at the time of the study included Nepal, India, Peru, Egypt, Morocco, Algeria or Libya, or any developing country when the planned trip was longer than a month in standard conditions, or longer than 10 days in poor conditions of hygiene. Breast-feeding or pregnant women, travelers on antibiotics or immunocompromised subjects were excluded. All travelers received clear information on the study and gave informed consent. The protocol was
A sample of the remaining capsules in the bottles, both from travelers who had kept them under 10° as recommended, and from those who had not, were sent for culture to the Microbiology Laboratory of the University Hospital of Lausanne. The contents were cultivated on gelose blood, TSA (tryptic soy agar), and MacConkey media, and determination of the number of bacteria (CFUs) was performed after dilution. A set of capsules of the same lot used in the study, was kept under strict observation of temperature conditions, and tested before and after the study, to serve as control.
Three methods were used to monitor compliance: a questionnaire, the pill count, and the MEMS. Compliance was evaluated based on the four criteria described under the vaccine description. The travelers with bottles opened more than three times, with an opening-time series corresponding to a schedule of alternate days, and a matching questionnaire were considered compliant.
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Statistical Analysis
The analysis used standard t-tests and chi-squared tests whenever appropriate. Results are presented as median values. Results From a total of 120 travelers enrolled, 5 were excluded from compliance analysis (4 due to MEMS technical failure, and 1 who didn’t return the questionnaire). The median age of the 115 travelers included was 32 years (range 19–72); there were 62 males and 53 females. Sixty (52.2 %) subjects were assigned to the oral information group and 55 (47.8 %) to the oral plus written information group. The gender, age and reason for traveling were similar in both groups. Ninety percent of them received malaria recommendations as well as the vaccine. Minor side effects were reported by 41/115 travelers (35.7%), usually gastrointestinal (n = 25), less frequently systemic (n = 16). The side effects were similar among females and males (n = 24/53 and 17/62 respectively, p = .005) and were less frequent after the second and third capsule. No difference in incidence of side effects was found between the 92% of travelers who had received other vaccines than the oral typhoid on the same day and those who had not (32/93 vs. 11/22, p = n.s) even for the systemic effects (14/93, vs. 2/22, p = n.s). Compliance in Taking the Capsules
The compliance according to the three different methods of evaluation is summarized in Table 1. Nearly all travelers took three capsules. Compared to the MEMS,
Table 1
the questionnaire evaluation overestimated compliance in taking the three capsules on alternate days (p = .01), and in keeping an interval with the meals as recommended. Compliance to all 4 criteria was complete in only 68% of travelers according to the questionnaire, and 53% according to the MEMS (p = .05). Figure 1 shows the distribution of the intervals between 2 doses, according to the MEMS, with a median value of 48 hours (range 20 minutes–18 days). Sixty seven percent of all the intervals were of 48 6 hours, 12% being shorter than 36 hours and 7% longer than 60 hours. Eighty-seven travelers (76%) took their dose faithfully on each alternate day (see Table 1), and 88% of their dose intervals were of 48 6 hours with none over 60 or under 36 hours. Although gender (female), a short trip (< 4 weeks), a hotel stay (as opposed to trekking), and the start of vaccine on the same day as the entry in the study, were factors for a better compliance, none reached statistical significance (data not shown). Receiving written information as well as oral information had a marginal but not significant impact on compliance (39/55 (71%) vs. 39/60 (65%), p = .5). Compliance in Storage and Effect on the Viability of the Vaccine
All travelers said they had kept the vaccine in the refrigerator. The median time the capsules spent out of refrigerator, due to transport was 90 minutes according to the questionnaire (range 15 minutes to 65 hours). However, 50 tags ( 42%) showed exposure to temperature higher than 10°C for more than 24 hours. No vaccine was stored at temperature greater than 30°C.
Comparative Evaluation of Compliance
Pill count n MEMS n Questionnaire n p value Other studies‡ Reference 11 Reference 14 Reference 15
Criterion 1:Taking All 3 Capsules (%)
Criterion 2: On Alternate Days (%)
Criterion 3: > 1 Hour Before Meal (%) *
100% 115/115 98% 113/115 100% 107/107
na
na
76% 87/115 89% 95/107 .01
61% 48/79§ 72% 67/93 .1
53% 42/79 68% 59/87 .05
91% 94% 90%
99% 78% 95%
82% 70% >90%>
98% 92% 99%
n = number of subjects; na = not available. *and more than 2 hours after a meal. † including keeping the vaccine under refrigeration (all travelers were compliant to this criterion). ‡ on 4 doses, by questionnaire only. § Analysis of data only when the dates for taking the capsules given in the questionnaire and the MEMS where the same.
Overall (%)†
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Figure 1 Distribution of dose intervals assessed by electronic monitoring. Most intervals (67%) were of 48 6 hours which indicate alternate day schedule as prescribed. In 19% of cases, the interval was either longer or shorter than 48 12 hours.
The number of colonies grown ranged from 1.8–19.0 108 (median 6.2 108) for the capsules kept at a temperature higher than 10°C for more than 24 hours (n = 44), compared to 1.3–16.0 108 (median 6.7 108) (p = .83) for the capsules kept at lower temperatures (n = 39). The control capsules kept strictly between 2 and 8°C showed a growth between 1.5 and 8.0 108 (median 5.1 108). Discussion The results of the present study demonstrate that although all patients apparently took their 3 capsules, the overall compliance with all recommendations is rather low at 53 %. Our observation also demonstrates that electronic monitoring of compliance provides more reliable information on compliance, as it allows precise analysis of the date and timing of each drug intake. Several studies have recently evaluated patient compliance in the use of the typhoid vaccine. A comparison between our results and other studies is presented in Table 1. When assessed by a questionnaire, the overall compliance measured in our study was similar (68%) to the results described by Rahman (70%),14 but clearly lower than the compliance reported in two other recent studies (82%,11 >90%15). The compliance in taking the 3 capsules was very good. Yet, the proportion of travelers committing compliance errors regarding the interval with meals is higher than in other studies, especially when assessed by MEMS which gives real time data. This can be partially attributed to the extra condition of taking the capsules at distance from a meal (either before or after the meal) which we required. The intervals with meals could have a theoretical influence on the vaccine efficacy if the presentation of the antigenic component of the vaccine is modified by the meals. There are no data about the effect of meals on the efficacy of the Ty21a typhoid
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vaccine, as all the studies have been done with the capsules or liquid formulation taken at a distance of a meal. The alternate day schedule was dutifully followed in 76% of cases and even better, 88% of their intervals were of 48 hours 6 hours, as assessed by the MEMS method. In our study, 12% of travelers had a prolonged interval between doses and 6% a shortened one. So far, no similar data are available in the literature, because few methods except electronic monitors can provide this kind of information. Little is known on the effect of the interval between the 3 doses and the efficacy of the vaccine. In a study in Chile, 3 doses taken with a 21 day interval were found to be less efficacious than doses given on alternate days,8 but in another study protection was not affected when the 3 doses were given at weekly intervals.24 All travelers kept the vaccine in the refrigerator (criterion 4) and although refrigeration was insufficient for 50 lots of vaccine, presumably because of poor capacity of the storage places, the viability of the capsule content was not affected by the temperature which never exceeded 30°C. Vaccine potency has been shown to be maintained even when stored at ambient temperatures for up to 7 days.15 In 17 cases the dates indicated for ingestion on the questionnaire showed the correct interval but did not match the dates as registered by the MEMS. Apparently the travelers knew what they were expected to do, but didn’t do it. In a previous study,25 adding written information to one to one counseling did not improve compliance more than counseling alone, but this may not necessarily be the case for short-term treatments.26 We describe a slightly better compliance of the group of travelers having received written information, but the groups are too small to show a significant difference. Measuring compliance is a difficult process as any method to measure it will introduce de ipso facto a general process reminder and improve compliance. Therefore any compliance study is likely to overestimate the compliance. In our study, the process reminder phenomenon would be similar in all groups, and the low compliance we found, would be even lower in reality. Questionnaire assessment relying on memory constantly overestimates compliance whereas electronic monitors, give the exact opening time and intervals between the taking of the capsules and are more accurate. Still, exact timing of the opening of the bottle is no proof for ingestion, and only direct observation, if feasible, would give true compliance. In conclusion, the majority of travelers take three capsules on alternate days, but many do not respect the other recommendations. Even when they know what to do, as shown by their answers in the questionnaire, they don’t do it. The problem is therefore as much a
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question of knowledge as a question of motivation. It is essential that the travelers understand the explanations and the purpose of the vaccination. The major strategies for improving adherence to treatment are to inform patients about illness and medication, to develop communication between health professionals and patients, to simplify treatment, to help the patient find convenient ways to follow the prescribed dosing regimen, and to make the patient take an active part in the treatment.25–28 References 1. Swiss Federal Office of Public Health. Fièvre typhoide et paratyphoide en Suisse 1988-1992. Bulletin de l’Office Fédéral de la Santé Publique 1993; 46:843–885. 2. Swiss Federal Office of Public Health, ed. Maladies infectieuses en Suisse 1997. Bern, Switzerland: Office Fédéral de la Santé Publique, 1999:5. 3. Reid D, Keystone JS. Health risks aboard : general considerations. In : Dupont HL, Steffen R, eds. Textbook of Travel Medicine and Health. Hamilton, Ontario : B.C. Decker Inc., 1997:5. 4. Acharya IL, Lowe MU, Thapa R, et al. Prevention of typhoid fever in Nepal with Vi capsular polysaccharide of Salmonella typhi. N Engl J Med 1987; 317:1101–1104. 5. Klugman KP, Gilbertson IT, Koornnof HS, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987; 2:1165–1169. 6. Wahdan MH, Serie C, Cerisier Y, et al. A controlled field trial of live Salmonella typhi strain Ty21A oral vaccine against typhoid: three year results. J Infect Dis 1982; 145:292–296. 7. Levine MM, Ferreccio C, Black RE, et al. Progress in vaccines against typhoid fever. Rev Infect Dis 1989; 11(3): S552–S567. 8. Levine MM, Ferreccio C, Black RE, Germanier R. Largescale field trial of Ty21a live oral typhoid vaccine in entericcoated capsule formulation. Lancet 1987; 1(8541):1049–1052. 9. Engels EA, Falagas ME, Lau J, Bennish ML. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity. BMJ 1998; 316:110–116. 10. Hirschel B, Wüthrich R, Somaini B, Steffen R. Inefficacy of the commercial live oral Ty21A vaccine in the prevention of typhoid fever. Eur J Clin Microbiol 1985; June:295–298. 11. Kaplan DT, Hill DR. Compliance with live, oral Ty21A typhoid vaccine. JAMA 1992; 267:1074. 12. Wolfe MS. Precautions with oral live typhoid (Ty21A) vaccine. Lancet 1990; 336:631–632. 13. Cramer JA. Overview of methods to measure and enhance patient compliance. In: Cramer JA, Spilker B, eds. Patient com-
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pliance in medical practice and clinical trials. New York: Raven Press, 1991:5–7. Rahman S, Barr W, Hilton E. Use of oral typhoid vaccine strain Ty21A in a New York State travel immunization facility. Am J Trop Med Hyg 1993; 48:823. Cryz SJ. Patient compliance in the use of Vivotif Berna® vaccine, typhoid vaccine, live oral Ty21A. J Travel Med 1998; 5:14–17. Sackett DL, Haynes RB,et al. Helping patients follow the treatments you prescribe. In: Clinical epidemiology: a basic science for clinical medecine. 2nd Ed. Boston: Little Brown and Co, 1991:258–261. Kruse W, Weber E. Dynamics of drug regimen complianceits assessement by microprocessor-based monitoring. Eur J Clin Pharmacol 1990; 38:561–565. Cramer JA. Microelectronic systems for monitoring and enhancing patient compliance with medication regimens. Drugs 1995; 49(3):321–327. Matsuyama JR, Mason BJ, Jue SG. Pharmacists’interventions using an electronic medication-event monitoring device’s adherence data versus pill counts. Ann Pharmacother 1993; 27:851–855. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed ? A novel assessment technique. JAMA 1989; 261(22):3273–3278. Pular T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets. Clin Pharmacol Ther 1989; 46:163–168. Fallab Stubi C-L, Zellweger JP, Sauty A, et al. Electronic monitoring of adherence to treatment in the preventive chemotherapy of tuberculosis. Int J Tuberc Lung Dis 1998; 2(7):1–6. McKenney JM, Munroe WP, Wright JT. Impact of an electronic medication compliance aid on long-term blood pressure control. J Clin Pharmacol 1992; 32:277–283. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunization against tyhpoid fever in Indonesia with Ty 21A vaccine. Lancet 1991; 338:1055–1059. Mullen PD, Green LW, Perstinger GS. Clinical trials of patient education for chronic conditions : a comparative metaanalysis of intervention types. Preventive Medecine 1985; 14:753–781. Haynes RB, McKibbon KA, Kanani R. Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medications. Lancet 1996; 348:383–386. Rogers HPG, Bullman WR. Prescription medicine compliance : a review of the baseline of knowledge-a report of the national council on patient information and education. J Pharmacoepidemiol 1995; 3(2):3–36. Roter DL, Hall JA, Merisca R, et al. Effectivness of intervention to improve patient compliance, a meta-analysis. Medical Care 1998; 36(8):1138–1161.
