Characteristics of American and African onchocerciasis
The American programme (OEPA) set out to eliminate onchocerciasis at its creation and pursued the objective persistently until it was achieved with remarkable success in one country after the other from 2007 to 2012 in a total of four countries [17]. The OEPA developed a strategy for pursuing interruption of transmission with ivermectin treatment which was based on studies in Guatemala [18]. The strategy consisted of treating 85% of the eligible population (equal to about 70% of the total population) with ivermectin biannually for 2–4 years to bring transmission down to zero and continuing that level of treatment to maintain zero transmission for 12 years, assuming that this would deplete the adult worm population and thus achieve elimination of transmission. Figure 2 shows the conceptual framework that was used for elimination of American onchocerciasis [19, 20]. Its logic is very similar to that of vector control by the OCP with the main difference being the required period of zero transmission, i.e. 12 versus 14 years.
Onchocerciasis in the Americas had the characteristic of being located in small foci, with a low to moderate intensity of infection and with a long history of control activities, mainly nodulectomy and vector control [11]. Vector migration was unknown and human migration did not play any significant role in spreading or even maintaining infection levels in other areas outside the foci. Furthermore, many of the vectors of onchocerciasis in the Americas are relatively inefficient compared to the vectors found all over Africa.
In a few focal areas in Africa where the endemicity of infection was similarly moderate, elimination by ivermectin treatment has also occurred, such as in the focus of Abu Hamad in Sudan using a combination of annual and biannual treatment [21], in the Kaduna focus in Nigeria using annual treatment [16], and in the river Geba valley in Guinea Bissau where elimination was already achieved in the 1990s after six years of annual ivermectin treatment only [22].
African onchocerciasis has variable epidemio-ecological settings [23,24,25] ranging from low and moderate intensity of infection to, and in particular, large and contiguous areas of extremely high intensity of infection maintained by highly efficient vectors. These vectors are also migratory and travel in some areas long distances of between 300 and 500 km assisted by prevailing winds [26, 27]. Millions of people are infected with many harbouring high to very high intensity of infection maintained by high vector human contact at or near vector breeding sites such as that found in the Vina valley in Cameroon and the Asubende focus in Ghana [28, 29] as well as many other holoendemic foci in Cameroon, the Democratic Republic of Congo, South Sudan and elsewhere.
From control to elimination
Many issues need to be addressed as African National Onchocerciasis Programmes change their objectives from control to elimination. The main issues are elaborated below.
Importance of precontrol endemicity levels
Entomological studies carried out in the course of the community trials on ivermectin demonstrated a remarkable reduction of transmission immediately following the administration of ivermectin to the population. However, unlike the studies in the Americas, the level of transmission that remained was still high. In the most thoroughly studied focus of Asubende the transmission returned to near its starting level 12 months after treatment and this finding was observed repeatedly in the first three years of ivermectin mass treatment [30]. Fitting epidemiological models to the results of these first studies provided the basis for the predictions of i) a gradual decline in transmission levels after repeated ivermectin treatment rounds, and ii) variation in the duration of ivermectin mass drug administration required to achieve elimination which ranged from 6 to more than 20 years depending on the level of endemicity at the onset of the intervention and the level of treatment coverage [10]. These predictions were later confirmed by research and evaluation data [10, 31].
Figure 3 shows the conceptual framework of onchocerciasis elimination by ivermectin mass treatment developed by APOC. It is fundamentally different from OCP’s framework for vector control which involved a rapid reduction in transmission to insignificant levels and maintaining that for 14 years till the parasite population had died out. Ivermectin treatment is less effective in reducing transmission but its comparative advantage, in addition to its microfilaricidal effect, is that it reduces the productivity and viability of the adult worms. It is the combination of these effects that determines the duration of treatment needed for elimination. In low endemic areas ivermectin treatment reduces already very low transmission to insignificant levels after only a few treatment rounds while its effect on the adult worms results in a shorter intervention period than for vector control, e.g. 6 years of annual treatment only in Rio Geba, Guinea Bissau. But in highly endemic areas longer intervention periods are needed than for vector control because of ivermectin’s more limited effect on transmission. The OEPA framework does not reflect these ivermectin dynamics but follows the vector control logic of the OCP.
Improving and expanding treatment coverage
The intervention strategy of CDTi remains applicable during the change from control to elimination. However, the first and foremost action should be to ensure that all transmission foci that are already under treatment have and maintain high treatment coverage. Not all areas that had been identified in the era of control to undergo treatment may have had high treatment coverage [10]. It is important that areas that have not had sufficiently high treatment coverage are rapidly identified so that reasons for the poor treatment coverage can be determined and corrective measures applied to improve coverage. Experiences in APOC have shown that such detection and the application of the appropriate corrective measures can be highly effective and result in an immediate boost in coverage [10]. Equally important is ensuring 100% geographic coverage to include all endemic communities. Experience has shown that some isolated communities in less accessible areas are sometimes overlooked in treatment programmes and that these may maintain a local transmission cycle [10]. Modern mapping methods using remote sensing data and spatial models with environmental covariates such as distance to river may help refine endemicity maps and ensure that all communities which need treatment are covered [5, 32].
Next is to identify all untreated areas where there is sustained local transmission. In this regard all historical data, including that from Rapid Epidemiological Mapping of Onchocerciasis (REMO), skin snip surveys and geographic information may help identify potential transmission areas. Surveys are needed to confirm local transmission. Most of such areas will be hypoendemic areas which would not have been treated in the control period as onchocerciasis did not constitute a serious public health problem or because the REMO method with its limitation in very low endemic areas could not have properly identified them. It is also important to underline the fact that a good part of the untreated hypoendemic areas would not be independent foci. They would be tail areas of more endemic foci that have now been eliminated after 10 to 20 years treatment which has also as a consequence eliminated infection in the tail areas. The first APOC experiences with recent surveys in such areas were consistent with this hypothesis and four of the first five surveyed potential transmission areas were shown to be now skin snip negative. In general, the procedure would be to identify potential endemic areas and then carry out surveys to validate the presence or absence of infection. Isolated cases of onchocerciasis infection do not constitute evidence of local transmission. Operational research and modelling will therefore be needed to further quantify thresholds for sustained local transmission in low endemic areas where CDTi is required. The challenge will be to decide how wide to cast the net and not to start an expensive and unwarranted undertaking.
Test methods to apply should include the newly recommended tests viz. serology for detecting OV16 antibodies as well as skin snip microscopy. The attributes of both tests are already known. The serological test is more sensitive at low endemicity levels. In its Rapid Diagnostic Test (RDT) format it is easy to use, provides rapid test results and has a specificity estimated at 97–98% [33]. The ELISA version is more sensitive than the RDT but less practical for large-scale surveillance [34]. However, these serological tests cannot be used to measure active infection levels required for impact assessment and measuring progress. The skin snip microscopy has the advantage of its use for estimating active infection which is vital for measuring the progress of the intervention towards the elimination end point. It is however invasive, less sensitive in very low infections and is being increasingly rejected by the populations. The use of the two tests together, as has been done by Pauline and Surakat [35, 36], under different epidemiological and operational conditions should provide an opportunity to establish the relationship between the two tests and provide an evidence-based approach for selection of the appropriate test for different settings.
Evaluation of progress towards elimination in all CDTi projects
Evaluation of the epidemiological impact of vector control during the OCP era was a key activity of the Programme. The process of skin snipping was applied to confirm the elimination of infection as a complement to the entomological evaluation which was applied to determine the interruption of transmission [6]. The importance of the use of two independent but complementary methods became even clearer in the OCP when the evidence of continued transmission at two foci in Burkina Faso was provided by epidemiological evaluations in the nineties, following interruption of transmission in the core area of the OCP. In the focus of Dienkoa, entomological evaluations missed a residual transmission which was detected by epidemiological evaluations. Vector control was subsequently extended to this area and effectively interrupted this local transmission. Likewise, a new breeding site with local transmission near two village settlements which had been created following the construction of a small dam on an affluent of the Bougouriba River, was not detected initially by entomological evaluations [37]. As the breeding site was therefore not covered by vector control, the resulting transmission maintained a prevalence of infection as high as 50% which, when vector control was stopped in this river basin, led to recrudescence of transmission. It was the epidemiological evaluation which brought conclusive evidence on the occurrence of the recrudescence.
With the advent of ivermectin the epidemiological evaluation process was modified accordingly in order that correct and appropriate interpretation of results would be obtained. The measure of active infection could be assessed meaningfully and comparatively only when skin snip was carried out a year after the last administration of ivermectin. The process is well established and despite all associated inconveniences, skin snip microscopy is still the epidemiologically most meaningful test that can be applied in the African setting.
In the context of elimination it is imperative to evaluate the progress towards elimination in all CDTi projects and take corrective action wherever needed. APOC has developed a methodology for the evaluation and interpretation of results which has been built on OCP’s methodology and experience. The details are provided in the publication by Tekle et al. [10] which reports on the current status of most of the CDTi projects of the former APOC. The recommended procedure is to carry out the first evaluation after six years of intervention to determine the decline in the prevalence of infection and Community Microfilarial Load (CMFL) of selected communities that may be sentinel villages or first line villages close to breeding sites, and to repeat the process every three to four years till the elimination threshold is reached. The measure can only be made with skin snip microscopy as serology cannot measure decline of infection levels. Furthermore, serology is only recommended for use in children less than ten years of age, which in onchocerciasis is the age group at lowest risk [38], whilst adults have the highest risk of infection and therefore form the most important age group for evaluation. The interpretation of the observed decline in the prevalence of microfilaria makes use of modelling to determine whether the decline is satisfactory or unsatisfactory, given the local endemicity before the intervention and treatment coverage [10]. In the event the decline is satisfactory the model is used to predict when elimination threshold will be reached. In the event of unsatisfactory decline it becomes necessary to identify the reasons in order to apply appropriate corrective measures.
Following the closure of APOC in 2015, after it had achieved its original objective, national onchocerciasis elimination committees have been established, as recommended by the WHO Guideline document of 2016 [39, 40], to coordinate the remaining activities in their countries. These committees need technical support for progress evaluation. The WHO guidelines document does not address the evaluation of progress towards elimination with ivermectin treatment nor was it its objective, and countries and partners working in the African sub-region need to urgently agree on standardised evaluation procedures and timelines.
Are measures being currently applied sufficient to achieve elimination by 2025?
CDTi projects for which the predicted end dates of treatment are beyond 2025 may require an alternative intervention strategy to accelerate infection decline towards elimination. One option may be biannual treatment. This should however not be done indiscriminately. In areas where transmission is seasonal it will be important to determine whether there is an advantage in changing from annual to biannual mass treatment. Cost implications of such decisions should be critically considered. Model predictions and epidemiological evidence indicate that 6 to 8 years of annual treatments will be sufficient to achieve elimination in hypoendemic areas [22, 41] and changing to biannual treatment in such areas would be completely unnecessary and a waste of resources. On the other hand, holo-endemic areas, where annual ivermectin treatment has occurred over the last 15–20 years without reaching the point of stopping intervention may consider implementing biannual treatment to accelerate the attainment of the end game. However, there is no guarantee that this will achieve timely elimination as models predicted that changing from annual to biannual treatments will only reduce the remaining number of years of treatment by one third [41]. In all these cases it remains important that a high treatment coverage rate is ensured.
Many have recommended vector control as an additional intervention method to accelerate the end game. In this connection, it is worth noting that an analysis of the combined use of vector control and ivermectin mass treatment in the OCP indicated that elimination could be achieved after 12 years, only two years shorter than the duration required by vector control alone [42]. This would suggest that vector control as an additional tool would not reduce the minimum duration of the intervention below 12 years as vector control has no effect on the longevity of the adult worm.
The application of a safe macrofilaricide that can sterilise or kill the adult worm and is suitable for mass administration would still be the ideal way to accelerate the attainment of elimination of human onchocerciasis, but such a drug continues to be elusive. However there might be cases where the use of doxycycline against wolbachia may be considered [43]. This could be applied in a setting where a small proportion of highly infected people in the population continues to maintain transmission in a focus. In this connection the results of new studies on the control of wolbachia with new antibiotics will be a welcome development. A phase III trial of moxidectin has confirmed with large numbers its superior capacity, compared to ivermectin, of significant delay of microfilarial repopulation of the skin [44]. Modelling this effect suggests that moxidectin might reduce the required duration of treatment by 30 to 40%, making it more cost-effective than biannual ivermectin treatment assuming the drug would be available free of charge [45]. For the moment we can only await its registration, which should provide a welcome alternative treatment in some of the areas where it would be required to accelerate the attainment of elimination.
There are also some onchocerciasis areas co-endemic with Loa loa where the current intervention method with ivermectin mass treatment is not safe [46]. Most of these areas had meso and hyperendemic onchocerciasis where ivermectin treatment was justified to prevent severe complications of onchocerciasis. However, in the remaining, largely hypoendemic foci, alternative or innovative approaches need to be applied to be able to achieve elimination in the countries where this phenomenon exists. Finally, there are still areas where there is political conflict with displaced populations which impedes smooth ivermectin mass treatment, notably in South Sudan and the Democratic Republic of Congo as well as in local areas in other countries. The CDTi strategy has proven effective and robust for these problem areas but additional financial and operational support will be needed if the elimination deadline of 2025 is to be met.
Vector and human migration play a very significant role in the transmission of onchocerciasis in West Africa, particularly in the former OCP countries. It is therefore important to look out for the phenomenon and take appropriate actions. At the beginning of the rainy season long distance migrating vectors from the south travel up to 500 km in north-easterly direction, assisted by winds, to populate rivers in the middle of the OCP area. They might bring infection from their source to areas that might not be under treatment or bring new infections to areas under treatment, which could seriously complicate local intervention efforts. The reverse occurs during the dry season with long distance migration from the north to the south-west [27]. It is therefore important to coordinate treatment and in fact organise treatment in the source area just before the start of vector migration to limit the effect of the phenomenon. An inter-country cooperation should be welcome to study and mitigate the phenomenon. This long distance vector migration is one of the possible reasons for the recent occurrence of recrudescence of infection in the already controlled area in the South-West of Burkina Faso after 20 years without local transmission [47]. Dispersal of vectors from one transmission focus to another can also occur locally and delay elimination efforts. This may be especially important across national borders necessitating particular cooperation. Also important is human migration, including for example, fishermen travelling along the river from untreated to treated areas and back to their origin. Human migration to mining areas and plantations occurs all the time. It is therefore important to pay particular attention to such phenomenon and ensure that migrating people get treatment where they have arrived in the event they have not been treated already at their place of origin.
When to stop control activities (vector control, ivermectin)
Vast experience with stopping vector control in the OCP over an area of 500 000 km2 demonstrated that prevalence and transmission do not have to be zero before interventions can be stopped but that low level thresholds exist when it is safe to stop intervention [13]. This process was supported by modelling and an entomological elimination threshold was given as < 0.5 infected fly per 1000 flies [48]. This threshold was subsequently also operationalised in the Americas. Follow up studies have confirmed the correctness of the OCP strategy [14, 29]. At the time of stopping vector control the average prevalence of microfilaria in the OCP was still 1.4%, consistent with modelling, and when vector control was stopped, there was no recrudescence of transmission. The study on the proof of principle on the feasibility of elimination of onchocerciasis with ivermectin mass treatment, carried out in Mali and Senegal, was also based on a stopping threshold above zero prevalence. After 15 to 17 years of annual (in two foci) and biannual (in one focus) of ivermectin treatment, the observed prevalence of infection (all ages) was 0.1–0.8% and the vector infectivity rate 0.0–0.46 infective flies per 1000. Again, when treatment was stopped, there was no recrudescence suggesting that the thresholds were valid for this epidemiological situation.
In contrast, the stopping point has not been clearly defined epidemiologically for serology. No rationale has been given for the threshold of 0.1% in children and now, as mentioned in the literature, the use of RDT is not feasible for that threshold given its specificity of 98% [35]. This anomaly is now being addressed by modelling and field studies but in the meantime the introduction of serology has delayed progress with stopping treatment which according to APOC evaluations should already be feasible for millions of people.