Drug-free Holidays: Compliance, Tolerability, and Acceptability of a 3-Day Atovaquone/Proguanil Schedule for Pretravel Malaria Chemoprophylaxis in Australian Travelers.

BACKGROUND: Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travelers. Pre-travel chemoprophylaxis may improve compliance by enabling "drug-free holidays." The standard treatment dose of atovaquone/proguanil (250 mg/100 mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. METHODS: Two hundred thirty-three participants were recruited from 4 specialized travel medicine clinics in Australia. Adults traveling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled and prescribed the 3-day schedule of atovaquone/proguanil, completed at least 1 day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. RESULTS: Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second days. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). CONCLUSIONS: The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travelers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travelers. CLINICAL TRIALS REGISTRATION: ACTRN12616000640404.

Immunogenicity after pre- and post-exposure rabies vaccination: A systematic review and dose-response meta-analysis.

BACKGROUND: There are a myriad of vaccine schedules for rabies pre- (PrEP) and post-exposure prophylaxis (PEP) that differ in the number and timedoses, number of visits, length of schedule, and route of administration. The objective of this study was to systematically review the evidence and investigate how thedifferences in schedules influence titres over time. METHODS: Four databaseswere searched from inception to January 2020 for rabies PrEP and PEP studies. Adose-response meta-analysis was utilised to pool geometric mean titres (GMT) over time. Subgroup analyses by route of administration, age group, and schedule were conducted. RESULTS: 80 studies met the inclusion criteria and contributed with 191 datasets and 12,413 participants. Both intradermal (ID) and intramuscular (IM) PrEP/PEP produce adequate GMTs. Significantly lower GMT levels were achieved in older (>50yrs) compared to younger (<50yrs) participants. Short 1-week schedules were as effective as longer schedules that can take between 3 and 12 weeks to complete. CONCLUSIONS: Several effective ID and IM schedules were identified, the selection of a schedule should take into account the patient's needs, costs, availability to return for subsequent doses, and the time required to complete the schedule. Older individuals warrant special attention as they develop lower antibody response.

Intradermal rabies pre-exposure vaccination schedules in older travellers: comparison of immunogenicity post-primary course and post-booster.

BACKGROUND: Intradermal (ID) rabies vaccination for pre-exposure prophylaxis (PrEP) has become increasingly popular; however, there is limited evidence about the effectiveness of different ID PrEP schedules in travellers aged > 50 years or their response to ID boosters. This study aimed to compare across different ID vaccine schedules and age groups the proportion of travellers who were seropositive after (i) primary course of ID PrEP and (ii) a booster. METHODS: Travellers who received ID PrEP at a travel medicine clinic in South Australia from 2000 to 2016 were included. Three schedules were examined: 1IDx3 (1 × 0.1 ml on days 0, 7, 21-28), 2IDx2 (2 × 0.1 ml on days 0, 7) and 4IDx1 (4x0.1 ml on day 0). The 4IDx1 is a non-standard schedule that has been previously explored in research settings, but not endorsed by WHO for PrEP. Antibody titres of ≥0.5 IU/ml were considered seropositive. The proportion seropositive after a primary course or post-booster was estimated for each schedule and age category. Predictors of seronegative status after a primary course were examined using multivariable logistic regression models. RESULTS: Overall, 835 travellers (median age 37.5 years; 37.1% > 50 years) were included in the analyses of seropositivity after a primary course. Another group of 771 travellers (median age 45.9 years; 43.5% > 50 years) was included in the analyses of seropositivity post-booster. The proportion seropositive after primary course was 92.5% (95%CI: 90.5-94.1%) and highest with the 1IDx3 schedule (93.4%; 95%CI: 91.4-95.0%). After adjusting for age and timing of the serology, the odds of seronegative status were four times higher (OR 4.17; 95%CI: 1.43-12.18) with the 4IDx1 schedule compared to 1IDx3. Overall, 98.7% (95%CI: 97.6-99.3%) were seropositive post-booster. Of 46 travellers who received a booster ≥3 years after PrEP, all were seropositive post-booster. CONCLUSIONS: In older travellers, the 1IDx3 schedule was the most effective, and a high proportion were seropositive post-booster even many years after a primary course.