Discussion
In 2008, the District of Kolofata was highly endemic for trachoma, with 24.0% of 1–9 years old children with TF and 7.5% with TI. The prevalence of active trachoma in this district justified the mass treatment of the entire population with 3 yearly rounds of azithromycin as part of the SAFE strategy.8 This study is the first to use topical azithromycin in mass treatment to reduce the prevalence of active forms of trachoma in an endemic population and included a surveillance survey 3 years after treatment mass cessation. After two annual rounds of mass treatment with topical azithromycin covering more than 90% of the entire population, an estimated TF prevalence of 3.1% was reached, and the WHO objective for elimination of active trachoma (prevalence <5%) was met. This was maintained 1 year after a third annual round, during which children were chosen among the most prevalent villages and among villages never tested. In parallel, the presence of TI was detected in less than 1% of subjects after the second and third annual mass treatments, which is encouraging since TI subjects are those most likely to develop cicatricial complications as the disease progresses.22 23
This study confirms previous results of a randomised clinical trial demonstrating that topical azithromycin 1.5% eye drops were at least as effective as the standard treatment in reducing the prevalence of active trachoma below 5%.15
A major concern when implementing a programme for eliminating trachoma is still to determine when to stop antibiotic treatment and preventive interventions24 25 and to determine the potential rebound in prevalence of active trachoma after interventions are stopped. As recommended in the WHO guidelines, a surveillance survey should be conducted at least 2 years after the impact survey to show that elimination targets is maintained in 1–9 years old children, as an indicator of trachoma elimination.26 Three to five years, or five to seven years of implementation of SAFE may be insufficient to achieve trachoma elimination as a public health problem in some endemic regions. Some severely affected districts in Ethiopia have been treated for a decade and have still not achieved the prevalence threshold of 5% for halting treatment.27 In our study, although active trachoma seemed to be eliminated after three annual rounds of treatment, it persisted in a few communities after treatment cessation. Three years after the last round of treatment, the surveillance survey using a two-stage sample procedure including the most prevalent villages and villages never tested before showed a TF prevalence of 5.2%, just above the WHO prevalence determined as the threshold necessary for the complete elimination of trachoma as a public health problem. Although the effectiveness of the SAFE strategy using oral azithromycin distribution has been demonstrated in numerous endemic populations worldwide,12 the effect of mass treatment at the village level is known to be heterogeneous.28 29 In low-endemic countries such as Gambia, a single oral dose of mass antibiotic treatment was sufficient to control C. trachomatis infection when combined with environmental conditions, such as good water supply and sanitation, with no re-emergence 5 years after treatment cessation.30 However, in more endemic regions, complete trachoma elimination in all communities may be difficult to achieve. Lakew et al showed that although trachoma prevalence was lowered to an average of 2.6% after four biannual treatments, prevalence had returned to 25.2% 2 years after the last treatment, indicating that if infection is not eliminated at the community level, it may return.29 In Mali, a 3-round mass treatment with oral azithromycin reduced the prevalence of active trachoma from 17% to less than 5%, but 3 years later trachoma started to re-emerge.31
Thus, the risk of re-emergence of trachoma once antibiotic pressure is removed is currently a major concern.25 Factors affecting the success of a Mass Drug Administration programme have been recently identified using a mathematical model of disease transmission.32 This included antibiotic treatment-related factors, such as coverage, dosing and frequency of distribution, and resistance. Antibiotic mass treatment coverage is an important issue since untreated individuals may serve as a source of community reinfection. WHO considered that coverage of 80% is acceptable, and increasing coverage above 90% in children does not appear to confer additional benefit.33 34 Nevertheless low coverage rates (<60%) of oral azithromycin mass treatment was reported in some highly endemic districts in Ethiopia.35 This can be due to a low acceptability of the oral azithromycin in some regions, in particular because of the fear of adverse events, as suggested previously.36 Oral azithromycin is generally well tolerated during mass treatment distribution,25 and has been associated with reduced all-cause and infectious childhood mortality.37 Nevertheless, up to 10% of people may experience side effects, primarily gastrointestinal disorders (abdominal pain, nausea and diarrhoea).38 Adverse effects in the first annual mass treatment round have been considered as a ‘great public health concern’ in some endemic regions which may compromise acceptability and treatment coverage.35 36 Moreover, in endemic communities, some individuals may be suspicious of taking an oral medicine for an eye disease. By contrast, we confirmed that topical azithromycin 1.5% was safe even in the youngest children of less than 6 months, as previously reported in different studies.15 39 Thus, topical azithromycin may be more easily accepted and could be proposed as an alternative when oral azithromycin is refused or contra-indicated. We assume that this could improve the coverage in some districts or communities where the trachoma elimination or control is difficult.
A recent meta-analysis showed that absence of latrines, dirty faces of children, and no reported use of soap for washing may be other important factors associated with active trachoma among children.40 In the Kolofata District, re-emergence was shown in several villages with impaired access to water due to borehole pump dysfunction or dry wells during a part of the year. Re-emergence of active trachoma above 10% in 1–9 years old children was also reported in several Kolofata District villages in which face washing among children was notably deficient.41 As in other endemic regions, while the S and A components have been widely implemented, evidence and specific targets are lacking for the F and E components, of which water, sanitation and hygiene are critical elements.5 The current recommendation for antibiotic mass treatment is to treat all the district community including infants of less than 6 months. It is known that the probability of being infected by C. trachomatis is strongly influenced by age. Children aged less than 1 year have the highest bacterial load, and thus should be treated.42 Oral azithromycin is not recommended in children under 6 months of age, and tetracycline ointment is typically used. In contrast, treatment with 1.5% azithromycin eye drops is possible since azithromycin 1.5% is well tolerated in infants from 1 day of age.43 Two times per day administration for 3 days with topical azithromycin 1.5% is also more convenient than tetracycline ointment, which requires two times per day instillations for 6 weeks.44 Thus, topical azithromycin may be proposed in place of tetracycline ointment to treat infants of less than 6 months.
Azithromycin 1.5% eye drops have other advantages compared with oral azithromycin. The possibility of inadequate and thus ineffective oral dose, when calculated on the height stick in children, may lead to insufficient dosing which may be an issue especially when the bacterial load is high.25 In addition, eye drops avoid the potential issue of reconstituting an oral solution in a remote area. The use of topical azithromycin should also substantially reduce the risk of bacterial resistance. By contrast, repeated oral azithromycin mass distribution may be detrimental if it results in the selection of macrolide-resistant pathogens, and there is epidemiological evidence suggesting that pharyngeal carriage of macrolide-resistant Streptococcus pneumoniae increases following repeated annual mass treatments with oral azithromycin for trachoma control, as recently reviewed by O’Brien et al.45
Oral azithromycin is generously donated through the International Trachoma Initiative for trachoma control programmes and topical azithromycin may be a promising alternative to oral azithromycin if treatment units are donated similarly, which was the case in the Kolofata Health District. In addition, beside the costs of the treatment units, a campaign to eliminate trachoma as a public health problem is probably more expensive initially when topical rather than oral azithromycin is used, since the former requires health resources over 3 days and the latter only 1 day. Further studies that take into account both short-term and long-term costs and benefits are necessary to determine the overall cost-effectiveness of topical versus systemic azithromycin mass treatment. To reduce costs in a campaign using topical medication, more community members could be trained to administer the final 2 days of drops; expanding community involvement might have the added benefit of increasing community commitment. Basic training of such community or family eye drop administrators could be done on site on the first day of administration: the health worker would train a member of each family or group of families and that person would administer drops on days 2 and 3. The feasibility and reliability of such a strategy remain to be investigated. In our situation, the administration of topical azithromycin to more than 100 000 inhabitants was successful and logistically and financially similar to other subsidised mass drug and vaccine administration activities held previously in the district.
The study has some limitations including the lack of a control group, meaning a comparison between topical and oral azithromycin mass treatment cannot be made directly. Other components of the SAFE strategy were also applied during the mass treatment campaign, including surgery of entropion-trichiasis, educational activities to promote individual (facial cleanliness) and collective hygiene, and environmental changes. During the mass treatment campaign, the Cameroon government installed borehole water pumps, while the OSF built some wells. However, it is not known to what extent these interventions helped in reducing trachoma prevalence. Persistence and transmission of trachoma is favoured where people live in poverty without safe water, sanitation and proper waste disposal, and the disease may return after antibiotic treatment if these conditions are not changed.5 41 Moreover, the clinical grading was based on clinical observations in accordance with the WHO simplified grading system.21 Specific biological tests using serological and PCR markers may be more reliable for testing ocular TF infection.46 Furthermore, by selecting one part of the sample from the most prevalent villages of the previous years and the other part from villages never surveyed before, the prevalence of active trachoma in the follow-up surveys (2011 and 2013) was no longer representative of the district level. Finally, standardisation for age as recommended by the recent WHO guidelines in 201818 was not possible. Such analysis was not planned at time of data recording, and data for the available census performed in the Kolofata District at that time could not be retrieved.
In conclusion, mass treatment with azithromycin eye drops was shown to be effective to reduce TF to a level ≤5% one year after a 3-round annual mass treatment in an endemic region at the district level. Longitudinal studies in multiple environments using epidemiologically rigorous sampling techniques are needed to ensure that the risk of re-emergence of disease and infection is not more likely than with oral azithromycin. Annual mass treatment of active trachoma with azithromycin 1.5% eye drops is feasible under field conditions, although the cost-effectiveness of topical azithromycin needs to be determined. In the meantime such topical azithromycin treatment could be proposed as an alternative treatment to tetracycline ointment or oral azithromycin (1) for treating young children of less than 6 months, (2) for treating others unable to take oral azithromycin, (3) for mass drug administration where the oral azithromycin donation programme is unavailable and (4) where the population mistrusts oral azithromycin given for an eye condition.
