CHAPTER FIVE

River Blindness: Mathematical

Models for Control and
Elimination
M.G. Bas
an~ ez*, 1, a, M. Walker*, a, H.C. Turner*, L.E. Coffengx,
S.J. de Vlasx, W.A. Stolkx
*Imperial College London, London, United Kingdom
x
University Medical Center, Rotterdam, Rotterdam, The Netherlands
1
Corresponding author: E-mail: m.basanez@imperial.ac.uk

Contents
1. Introduction 250
1.1 Life cycle of Onchocerca volvulus 250
1.2 Control and elimination of onchocerciasis and the role of mathematical 251
modelling
1.2.1 The Onchocerciasis Control Programme in West Africa (OCP, 1974e2002) 252
1.2.2 The African Programme for Onchocerciasis Control (APOC, 1995e2015) 255
1.2.3 The Onchocerciasis Elimination Program for the Americas (OEPA, 1993epresent) 256
1.2.4 Accelerating the control and elimination of onchocerciasis 257
1.3 Alternative treatment strategies 257
1.3.1 Increasing coverage, adherence and frequency of ivermectin treatment 257
1.3.2 Other microfilaricidal therapies (moxidectin) 258
1.3.3 Macrofilaricidal therapies (doxycycline) 258
1.3.4 Vector control 259
1.4 The NTD Modelling Consortium and review aims 259
2. The Models 260
2.1 EPIONCHO 260
2.1.1 Parasite population regulation in humans 261
2.1.2 Parasite population regulation in vectors 269
2.1.3 Pretreatment parasite dynamics 270
2.1.4 Posttreatment parasite dynamics 272
2.1.5 Model outputs 280
2.2 ONCHOSIM 281
2.2.1 Human population demography 281
2.2.2 Parasite population regulation in humans 282
2.2.3 Parasite population regulation in vectors 286
2.3 Comparison between EPIONCHO and ONCHOSIM 290

a
These authors contributed equally to the work.
Advances in Parasitology, Volume 94
© 2016 Elsevier Ltd.
j
ISSN 0065-308X
http://dx.doi.org/10.1016/bs.apar.2016.08.003 All rights reserved. 247
248 ~ez et al.
M.G. Bas
an

3. Model Validation 302

3.1 EPIONCHO 302
3.2 ONCHOSIM 303
4. Modelling Current Treatment Strategies 304
4.1 Defining elimination endpoints 305
4.2 Treatment with ivermectin 306
4.2.1 Epidemiological and programmatic variables 307
5. Modelling Alternative Intervention Strategies 309
5.1 Moxidectin treatment 312
5.2 Macrofilaricidal treatment 312
5.3 Vector control 314
5.4 An onchocerciasis vaccine 315
6. Economic Evaluations 315
6.1 Burden of disease 316
6.1.1 Blindness and visual impairment 316
6.1.2 Skin disease 317
6.1.3 Excess mortality 317
6.2 Costing intervention strategies 318
6.3 The economics of elimination and eradication 318
7. Challenges and Future Directions 319
7.1 Relationship between operational endpoints, transmission breakpoints and 320
stochastic fade-out
7.2 Estimating basic and effective reproduction ratios 321
7.3 Modelling the diagnostic performance of the skin snip method and serological 324
assays in near-elimination scenarios
7.4 Modelling hypoendemic onchocerciasis 326
7.5 Spatial models of onchocerciasis transmission 327
8. Conclusions 328
Acknowledgements 329
References 329

Abstract
Human onchocerciasis (river blindness) is one of the few neglected tropical diseases
(NTDs) whose control strategies have been informed by mathematical modelling.
With the change in focus from elimination of the disease burden to elimination
of Onchocerca volvulus, much remains to be done to refine, calibrate and validate
existing models. Under the impetus of the NTD Modelling Consortium, the teams
that developed EPIONCHO and ONCHOSIM have joined forces to compare and
improve these frameworks to better assist ongoing elimination efforts. We review
their current versions and describe how they are being used to address two key ques-
tions: (1) where can onchocerciasis be eliminated with current intervention strategies
River Blindness 249

by 2020/2025? and (2) what alternative/complementary strategies could help to

accelerate elimination where (1) cannot be achieved? The control and elimination
of onchocerciasis from the African continent is at a crucial crossroad. The African Pro-
gramme for Onchocerciasis Control closed at the end of 2015, and although a new
platform for support and integration of NTD control has been launched, the
disease will have to compete with a myriad of other national health priorities at a
pivotal time in the road to elimination. However, never before had onchocerciasis
control a better arsenal of intervention strategies as well as diagnostics. It is, therefore,
timely to present two models of different geneses and modelling traditions as they
come together to produce robust decision-support tools. We start by describing
the structural and parametric assumptions of EPIONCHO and ONCHOSIM; we
continue by summarizing the modelling of current treatment strategies with annual
(or biannual) mass ivermectin distribution and introduce a number of alternative stra-
tegies, including other microfilaricidal therapies (such as moxidectin), macrofilaricidal
(anti-wolbachial) treatments, focal vector control and the possibility of an onchocer-
ciasis vaccine. We conclude by discussing challenges, opportunities and future
directions.

List of Abbreviations
ABR Annual biting rate
APOC African Programme for Onchocerciasis Control
ATP Anniual transmission potential
CDTI Community-directed treatment with ivermectin
CMFL Community microfilarial load
DALY disability-adjusted life years
ESPEN Expanded Special Project for Elimination of Neglected Tropical Diseases
MDA Mass drug administration
mf Microfilariae
mg Milligram
MTP Monthly transmission potential
NBD Negative binomial distribution
NTD Neglected tropical disease
OCP Onchocerciasis Control Programme in West Aftica
OEPA Onchocerciasis Elimination Program for the Americas
PCT Preventative chemotherapy
pOTTIS Provisional Operational Thresholds for Treatment Interruption and commence-
ment of Surveillance
REMO Rapid epidemiological mapping of onchocerciasis
R0 Basic reproduction number
SAE Severe adverse event
s.l. Sensu lato
s.s. Sensu stricto
ss Skin snip
TOVA The Onchocerciasis Vaccine for Africa Initiative
WHO World Health Organization.
250 ~ez et al.
M.G. Bas
an

1. INTRODUCTION
Human onchocerciasis, a neglected tropical disease (NTD) also known
as ‘river blindness’, is a parasitic infection caused by the filarial nematode
Onchocerca volvulus Leuckart (Filarioidea: Onchocercidae). Transmission
among hosts occurs via the bites of Simulium Latreille flies (Diptera: Simulii-
dae). The name river blindness illustrates that the worst sequela of the infec-
tion is the loss of vision and that the vectors breed in fast flowing water.
Onchocerciasis has been endemic in 27 sub-Saharan African countries, the
Yemen and 6 Latin American countries, with an estimated 37 million people
infected and 90 million at risk, 99% of them in Africa (APOC, 2005). For a
map of the global distribution and status of control as of 2006 see Bas
an ~ez
et al. (2006). Due to the efforts of intervention programmes such as the
Onchocerciasis Control Programme in West Africa (OCP), the African Pro-
gramme for Onchocerciasis Control (APOC) and the Onchocerciasis Elim-
ination Program for the Americas (OEPA) (Richards et al., 2001),
onchocerciasis has been successfully eliminated in some foci of Mali, Senegal
(Diawara et al., 2009; Traore et al., 2012) and Nigeria (Tekle et al., 2012), in
Mexico (Rodríguez-Pérez et al., 2015), in the northern foci of Venezuela
(Convit et al., 2013), in Colombia (West et al., 2013) and Ecuador (Lovato
et al., 2014). From the early years of the OCP until present, mathematical
modelling has played an important role to support planning, evaluation
and decision making in large-scale control programmes (Remme, 2004a;
~ez and Ric
ardez-Esquinca, 2001). In this chapter we will review the
Bas
an
contribution that mathematical models have made to our understanding of
the epidemiology, population biology, transmission dynamics, control and
feasibility of elimination of onchocerciasis with current and novel interven-
tion tools and strategies.

1.1 Life cycle of Onchocerca volvulus

In this section we describe some of the salient features of the parasite’s life
cycle that determine the dynamics of the infection. The adult worms
(macrofilariae) are dioecious (separate sexes) and, therefore, reproduction
requires mating of male and female worms. (In modelling terms, a mating
probability e the probability that female worms are mated e needs to be
included.) Macrofilariae live in subcutaneous palpable nodules called
onchocercomata and in deeper, inaccessible worm bundles, for an average
of 10  3 years (Duerr et al., 2003; Plaisier et al., 1991a). This is the
River Blindness 251

longest-lived parasite stage and mostly responsible for the protracted dynamics
characteristic of onchocerciasis. Females are fertilized by males during distinct
reproductive cycles, with three to four such cycles occurring each year
(Schulz-Key and Karam, 1986). Therefore, unlike other nematodes, female
O. volvulus oscillates between being nonfertile and being fertile, producing
thousands of embryos (microfilariae) throughout their fertile cycles and
millions during their lives. A heavily infected person may harbour 50e
200 million of them. Microfilariae live for about 12e15 months in the skin
(Duke, 1993). If they are ingested by simuliid species competent for O.
volvulus, they will develop into infective L3 larvae during the extrinsic incu-
bation period, whose duration e in the poikilotherm insect vectors e is tem-
perature dependent, with a mean of 8  3 days (Cheke et al., 2015). L3 larvae
enter another human via the bite wound made when the blackfly next feeds
and mature into reproductive adult stages during the intrinsic incubation
period within 12e18 months (Duke, 1991; Nelson, 1991). The prepatent
period from infection to production of a sizeable microfilarial population,
detectable by the typical skin snip diagnostic method, can be as long as 3 years
(Prost, 1980). For a pictorial representation of the life cycle see Fig. 1.
Those microfilariae not taken up by the vectors die within skin and eye
tissues, provoking an immune response to the released somatic antigens,
which leads to the inflammatory lesions that underlie onchocerciasis-
associated pathology. In addition, proinflammatory cytokines released from
Wolbachia bacteria that live in mutualistic symbiosis with the worms generate
inflammatory responses that are also involved in the cutaneous and ocular
pathogenesis of the disease (Brattig, 2004; Saint André et al., 2002).

1.2 Control and elimination of onchocerciasis and the role of

mathematical modelling
Onchocerciasis is an exemplary case among human helminthiases in which
mathematical models have been used to inform control policy (e.g., inter-
vention strategy, programme duration, frequency of application, health
impact) since the early stages of their implementation (Bas
an ~ez et al.,
2012), due to a long-lasting and fruitful partnership between research and
control activities (Remme et al., 1995; Remme, 2004a). In the next sections
we review the three major onchocerciasis control and elimination initiatives
that have been put in place worldwide and highlight the questions addressed
by models within these programmes. We proceed to discuss how best can
models work together to tackle remaining challenges within the current
impetus for transmission interruption and parasite elimination at a global
252 ~ez et al.
M.G. Bas
an

Figure 1 Life cycle of Onchocerca volvulus. Mean dimensions of parasite stages are:
adult females, 35e70 cm  400 mm; adult males, 2e4 cm  150e200 mm; microfilar-
iae, 250e360  5e9 mm; L1 larvae, 200 mm  12 mm (front) and 20 mm (rear); L3,
440e700  20 mm. L1 larvae moult into L2, preinfective larvae, and L2 into L3, infective
larvae. (Illustration: Giovanni Maki, derived from a CDC image at http://www.dpd.cdc.
gov/dpdx/HTML/Filariasis.htm) (Bas
an ~ez et al., 2006).

scale (World Health Organization, 2012; African Programme for

Onchocerciasis Control, 2012) and particularly in Africa (World Health
Organization/African Programme for Onchocerciasis Control, 2015).

1.2.1 The Onchocerciasis Control Programme in West Africa (OCP,

1974e2002)
The OCP started as a vector control programme aiming to eliminate
the public health burden of blinding onchocerciasis in savannah areas of
River Blindness 253

West Africa. From a core, original area of 654,000 km2 in nine countries, it
was successively extended to 1,300,000 km2 in 11 countries to prevent rein-
vasion by flies from uncontrolled areas (Boatin, 2008; Boatin and Richards,
2006). O’Hanlon et al. (2016) have used model-based geostatistics to pro-
duce maps of the initial microfilarial prevalence in the OCP. The OCP
initially aimed at interrupting transmission by reducing simuliid populations
(via weekly aerial distribution of larviciding insecticides in the blackfly
breeding sites) for long enough to curtail acquisition of new infections
and let the adult worm population die of natural attrition.
Towards the end of the 1980s, the microfilaricidal drug ivermectin
(MectizanÔ ) was licensed for human use after a series of clinical trials, which
have been metaanalysed using mathematical modelling by Bas
an ~ez et al.
(2008). A standard dose of ivermectin (150 mg/kg of body weight, orally)
causes a 98e99% reduction in skin microfilarial density within 1e2 months
after treatment (due to the microfilaricidal effect of the drug), with new
microfilariae gradually repopulating the skin (as female worms resume the
production of live microfilariae) from the third month posttreatment on-
wards. In addition to reducing transmission from humans to vectors, the
microfilaricidal effect of ivermectin helps to prevent the morbidity associated
with onchocerciasis, for which microfilariae are essentially responsible.
Therefore, ivermectin is a drug in the arsenal of the so-called preventive
chemotherapy treatment (PCT), a strategy endorsed by the World Health
Organization (WHO) to tackle some of its prioritized NTDs (World Health
Organization, 2006). The OCP conducted community trials of mass iver-
mectin distribution in Ghana, showing that it was feasible and safe to admin-
istrate treatment at a large scale (Remme et al., 1989, 1990b; Alley et al.,
1994). In 1987, Merck & Co. Inc. announced the donation of ivermectin
for as long as necessary to combat river blindness (Colatrella, 2008). The
OCP adopted an annual treatment strategy by 1989, which was used to
complement vector control in some areas and as the only intervention in
most of the extension areas (Boatin, 2008). In some of these (extension)
foci, mass ivermectin treatment was provided biannually (6-monthly)
(Diawara et al., 2009). Ivermectin mass treatment was initially delivered
by mobile teams and nongovernmental organizations and later via commu-
nity-based distribution, overseen by trained nurses and/or technicians.
Finally, this evolved over several years into community-directed treatment
with ivermectin (CDTI), the preferred mode of drug delivery e a strategy
pioneered by APOC to enhance its long-term sustainability (Boatin,
2008). In 1995 Kim and Benton (1995) estimated that between 1974 and
254 ~ez et al.
M.G. Bas
an

2002, the overall operations of the OCP would have averted 593,440 cases
of blindness.
During the earlier (vector control) stages of the OCP, mathematical
models were used to determine: (1) the threshold biting rates of the savannah
members of the Simulium damnosum sensu lato (s.l.) complex, below which
endemic onchocerciasis would not be able to persist (Dietz, 1982), (2) the
dynamics of recolonization by blackflies of breeding sites after spraying of
the larvicides (Birley et al., 1983) and (3) the duration of vector control
that would be necessary to interrupt transmission and prevent recrudescence
(Plaisier et al., 1991b). It was estimated that at least 300e700 bites per person
per year by S. damnosum sensu stricto/S. sirbanum (depending on whether the
local vector population was more or less anthropophagic) would be neces-
sary for the basic reproduction ratio (Section 7.2), R0, of the parasite to be
one or greater (Dietz, 1982). These figures were confirmed by subsequent
modelling studies using a precursor of the EPIONCHO model (described
in Section 2.1) (Bas
an~ez and Boussinesq, 1999) and a refinement of the Dietz
(1982) model (Duerr and Eichner, 2010). In the absence of immigration of
infected humans or invasion by infected flies, the microsimulation model
ONCHOSIM (developed in the early 1990s by Plaisier et al., 1990;
described in Section 2.2) predicted that 14 years of full-scale vector control
would be required to reduce the risk of recrudescence to less than 1%
(Plaisier et al., 1991b). These projections were confirmed by the epidemio-
logical trends presented by Hougard et al. (2001).
As the OCP integrated vector control with ivermectin distribution,
ONCHOSIM was used to estimate the reduction in programme duration
that could be achieved by combining vector control with ivermectin mass
treatment (Plaisier et al., 1997), as well as to assess the feasibility of elimi-
nating onchocerciasis with ivermectin treatment alone (Winnen et al.,
2002). It was concluded that 20e25 years of treatment at a high coverage
would be required in foci with very high precontrol endemicity levels to
achieve elimination. These projections were confirmed by subsequent
modelling studies (Turner et al., 2013a; Coffeng et al., 2014a; Stolk
et al., 2015). Presently, although onchocerciasis-associated morbidity has,
by and large, been eliminated in most of the former OCP area, transmission
remains in some foci and countries (due to conflict interrupting control
operations, incomplete geographical coverage, and suboptimal responses
to ivermectin treatment, among other factors) (Frempong et al., 2016;
Hodges et al., 2011; Lamberton et al., 2015; Lloyd et al., 2015; Osei-
Atweneboana et al., 2007).
River Blindness 255

1.2.2 The African Programme for Onchocerciasis Control (APOC,

1995e2015)
In view of the potential of ivermectin for onchocerciasis control if high
levels of geographic and therapeutic coverage could be achieved, APOC
was launched in 1995 (Remme, 1995) under the auspices of the WHO to
cover the remaining endemic African countries outside the OCP. Countries
and areas in need of treatment were mapped through rapid epidemiological
mapping of onchocerciasis (REMO) (Ngoumou and Walsh, 1993; Noma
et al., 2002). Zouré et al. (2014) have used model-based geostatistics to
map the prevalence of onchocercal nodules (the basis of REMO) in the
APOC area. APOC’s original objective was to establish, within an initial
period of 12 years, effective and self-sustainable CDTI projects in order to
control morbidity from onchocerciasis (World Health Organization, 1996;
Amazigo et al., 2002). CDTI was implemented in 16 of 20 mapped
countries, covering endemic areas inhabited by roughly 71.5 million people
in 1995 (Coffeng et al., 2013a). APOC delivered its first treatments through
CDTI in 1997 (80,000 treatments). The programme was progressively
scaled up to reach an overall therapeutic coverage of about 73% in 2010
(75.8 million treatments). By the end of 2013, around 100.7 million people
in 132,919 communities were receiving ivermectin (World Health
Organization/African Programme for Onchocerciasis Control, 2014). In
2014, the number of people receiving ivermectin had increased to around
112.5 million people, despite the fact that no treatments occurred in Liberia
and Sierra Leone, due to the Ebola outbreak, with an estimated coverage of
78% by 2015, the final year of the programme (World Health Organization/
African Programme for Onchocerciasis Control, 2015).
In 2010, and motivated by the successful elimination of the infection in
some foci of Mali and Senegal (Diawara et al., 2009) e within the western
extension of the OCP and without vector control e APOC shifted its goals
from the control of onchocerciasis morbidity to elimination of the parasite
reservoir, where feasible, with annual (or biannual) ivermectin MDA
(African Programme for Onchocerciasis Control, 2010). Other examples
of onchocerciasis elimination in APOC projects provided further evidence
to support the feasibility of this change in programme objectives (Tekle
et al., 2012; Higazi et al., 2013).
ONCHOSIM was used to model the impact, on achieving elimination
in APOC settings, of increasing the frequency of ivermectin mass treatment
(Coffeng et al., 2014a). Doubling the frequency of treatment from yearly to
6-monthly or 3-monthly was predicted to reduce remaining programme
256 ~ez et al.
M.G. Bas
an

duration by about 40% or 60%, respectively. Using data on precontrol

prevalence of infection and MDA coverage, trends in infection, visual
impairment and blindness (eye disease) and severe itch (skin disease) between
1995 and 2010 were simulated, estimating that during that period
8.2 million disability-adjusted life years (DALYs) due to onchocerciasis
were averted in APOC areas, at a nominal cost of about US$257 million.
The ONCHOSIM model was also used to project health impact and cost
for the final period of 2011e2015, anticipating that APOC will have averted
another 9.2 million DALYs at a nominal cost of US$221 million during its
final phase (Coffeng et al., 2013a).

1.2.3 The Onchocerciasis Elimination Program for the Americas

(OEPA, 1993epresent)
Since its inception in 1993 OEPA was conceived as an elimination
programme (both of the morbidity associated with onchocerciasis and of
the transmission and reservoir of infection) in its six constituent Latin Amer-
ican countries (Blanks et al., 1998; Sauerbrey, 2008). This approach was
based on the perceived strength and visibility that a cohesive regional
onchocerciasis initiative would have (for otherwise a low-priority disease
in the continent). Biannual (6-monthly) ivermectin mass treatment was
adopted as the main strategy, since epidemiological and entomological
studies conducted in areas where the vector was S. ochraceum s.l. indicated
that twice-yearly treatment could lead to interruption of transmission
despite high vector density and initial endemicity, provided high coverage
levels could be achieved (Collins et al., 1992; Cupp et al., 1992). In some
communities with high precontrol onchocerciasis endemicity and
transmission intensity, a regimen of 3-monthly (quarterly) ivermectin treat-
ments was implemented, helping to accelerate interruption of transmission
(Rodríguez-Pérez et al., 2008).
The SIMON simulation model, originally developed for forest oncho-
cerciasis in Sierra Leone (Davies, 1993) was adapted for the Americas
(SIMON-A), and although not formally published, has been used to inform
OEPA’s regional strategy. All versions of the SIMON-A model indicate that
at the end of the treatment programme, there will be a period of 3e5 years
during which some members of a community will continue to be infected at
a low parasite level, giving an indication of the period necessary for post-
treatment surveillance (Rodríguez-Pérez et al., 2011). A precursor of the
deterministic EPIONCHO model was used to investigate the role of regular
nodulectomy campaigns (excision of palpable onchocercomata) in addition
River Blindness 257

~ez
to that of ivermectin for the control of onchocerciasis in Mexico (Bas
an
and Ric
ardez-Esquinca, 2001).
Presently, onchocerciasis transmission has been eliminated from
Colombia (West et al., 2013); Ecuador (Lovato et al., 2014), Mexico
(Rodriguez-Pérez et al., 2015) and northern Venezuela (Convit et al.,
2013), but it remains in the hard-to-reach indigenous Yanomami popula-
tion inhabiting the Amazon rainforest straddling Venezuela and Brazil
(Botto et al., 2016).

1.2.4 Accelerating the control and elimination of onchocerciasis

In January 2012 Dr. Margaret Chan, Director General of the WHO, pre-
sented a roadmap for accelerating work to overcome the global impact of
NTDs. This announcement inspired the launching of the London Declara-
tion on NTDs and set targets and milestones for elimination during the period
2015e2020 (Uniting to Combat Neglected Tropical Diseases, 2012; World
Health Organization, 2012). Regarding onchocerciasis, regional elimination
in the Americas was anticipated for 2015 (achieved in most foci with the
exception of the hard-to-reach Yanomami population of the Amazonian
focus (World Health Organization, 2014; Botto et al., 2016). For Africa,
the roadmap set goals of elimination by 2020 in selected African countries
and by 2025 in 80% of African countries (African Programme for Onchocer-
ciasis Control, 2012). However, modelling work has indicated that in some
areas with high precontrol endemicity (and hence with conditions propitious
to intense transmission), annual CDTI e the predominant control strategy in
Africa e may not be sufficient for the achievement of the elimination goals in
the proposed time frameworks (Turner et al., 2013a; Coffeng et al., 2014a;
Stolk et al., 2015). For these areas, as well as for others, lagging behind the
elimination goals, implementation of alternative or complementary strategies
may be necessary (World Health Organization/African Programme for
Onchocerciasis Control, 2015). In the next section we describe some of these
strategies, which will be revisited later in the chapter within the context of our
current modelling work to provide rigorous and quantitative decision-
making support to the elimination endeavour.

1.3 Alternative treatment strategies

1.3.1 Increasing coverage, adherence and frequency of ivermectin
treatment
If programmatic difficulties have slowed down progress, an increased effort
to improve treatment coverage and adherence may be necessary. For areas
258 ~ez et al.
M.G. Bas
an

starting to implement CDTI or needing to switch strategies, the most

obvious option may be increasing the frequency of ivermectin treatment
(to twice or four times per year if possible), as highlighted by the Latin
American experience. In Section 6, we discuss the effectiveness and cost
effectiveness of these strategies as explored by combining epidemiological
and cost data with mathematical models (Coffeng et al., 2014a; Turner
et al., 2013b; Turner et al., 2014c).

1.3.2 Other microfilaricidal therapies (moxidectin)

Moxidectin (a macrocyclic lactone derivative of the milbemycins and not of
the avermectins, as is the case for ivermectin) has not yet been licensed for
human use. However, phase II and phase III clinical trials have been con-
ducted in Africa to assess its safety and efficacy for the treatment of human
onchocerciasis (Awadzi et al., 2014). Motivated by these studies, modelling
has been used to investigate its potential use in MDA programmes for the
control and elimination of O. volvulus infection in comparison with iver-
mectin (Turner et al., 2015a). Salient results will be discussed in Section 5.1.

1.3.3 Macrofilaricidal therapies (doxycycline)

If attainment of high levels of treatment coverage and adherence has been
hindered by coendemicity of onchocerciasis and loiasis (caused by the filarial
nematode Loa loa), as is the case in some forest foci of Cameroon (Wanji
et al., 2015a,b), microfilaricidal MDA treatment with ivermectin (or mox-
idectin) may be contraindicated in some epidemiological settings. This is
because severe adverse events (SAEs), such as encephalopathy, have been
reported following ivermectin treatment in a proportion of individuals
with high L. loa microfilaraemia (Mackenzie et al., 2007). Maps of loiasis
prevalence distribution have been developed to aid understanding of the
true extension of the problem (Zouré et al., 2011). In some of these areas
doxycycline may be deployed on a test-and-treat basis. Doxycycline is effec-
tive against adult O. volvulus by depleting the worms from their Wolbachia
endosymbiotic bacteria, essential for parasite reproduction and survival
(Taylor et al., 2014). Although not microfilaricidal, O. volvulus microfilariae
from treated individuals do not develop at their normal rate in their simuliid
vectors, potentially impacting on transmission (Albers et al., 2012). Besides,
L. loa does not contain Wolbachia, rendering doxycycline safe for treatment
of coinfected patients. However, key barriers to using doxycycline as an
MDA strategy for widespread community-based control are the logistics
of a relatively lengthy course of treatment (4e6 weeks) and
River Blindness 259

contraindications in children under eight years and in pregnancy. Mathe-

matical modelling has been used to quantify the macrofilaricidal efficacy
of doxycycline (Walker et al., 2015) and will be discussed in Section 5.2.

1.3.4 Vector control

Large-scale vector control, by weekly spraying of blackfly breeding sites
with larvicidal insecticides, as it was successfully implemented by the OCP
(Hougard et al., 2001), has been modelled using ONCHOSIM as an instan-
taneous reduction in the level of blackfly biting followed by immediate
recolonization (and resumption of blackfly biting) following cessation of
control (Plaisier et al., 1997; Alley et al., 2001). Under these assumptions,
large-scale vector control has been shown to be highly complementary to
annual ivermectin MDA, such that combined strategies e even in highly
endemic settings e can achieve elimination with a lowered risk of recrudes-
cence in little over 10 years (Plaisier et al., 1997).

1.4 The NTD Modelling Consortium and review aims

Both the WHO roadmap and the London Declaration on NTDs provided
the impetus for the establishment, in 2014, of the Bill & Melinda Gates
Foundation-supported NTD Modelling Consortium (http://www.
ntdmodelling.org/). The motivation of the consortium lies in the recogni-
tion that many urgent policy issues concerning the control and elimination
of NTDs can only be answered through the use of quantitative tools, and
that this can only be truly achieved through strong collaborations between
modellers, epidemiologists, policy makers and field epidemiologists (Bas
an ~ez
and Anderson, 2015).
The issues posed by the NTD Modelling Consortium regarding oncho-
cerciasis elimination can be distilled into two main questions: (1) where (and
under which epidemiological scenarios) do models predict that onchocerci-
asis can be eliminated with current strategies by the timelines proposed in the
WHO (2012) roadmap and (2) in those scenarios where elimination cannot
be achieved using the current strategy, which (and where) alternative and
complementary intervention strategies should be deployed to facilitate/
accelerate progress towards elimination. These questions, and the modelling
work necessary to address them, are particularly poignant at a time when
onchocerciasis control and elimination activities are being devolved to the
national health programmes and systems of endemic countries in Africa
following APOC’s closure at the end of 2015.
260 ~ez et al.
M.G. Bas
an

Therefore, this chapter aims to review the progress made towards

addressing these questions and supporting the WHO (2012) goals, and to
highlight areas of future work. We commence by reviewing the structure
of the two main onchocerciasis models that have been included under the
umbrella of the NTD Modelling Consortium. We do this in order to pro-
vide, in a single document, the formal description of both models in their
current phase of development. We continue by comparing some of their
salient features in the context of providing reliable elimination projections
and by describing the efforts that have been made thus far to validate such
models. We proceed by reviewing the modelling of current interventions
as well as of alternative treatment strategies. Finally, we discuss the challenges
faced in addressing the questions posed by the NTD Modelling Consortium
and indicate future research directions that are essential to refine our models
in order to best serve onchocerciasis control and elimination efforts in areas
of ongoing transmission.

2. THE MODELS
2.1 EPIONCHO
EPIONCHO is a deterministic, population-based model that uses
partial differential equations to describe, with respect to time and host
age, the rate of change of the mean numbers of nonfertile, N, and fertile,
F, adult female worms per host; of microfilariae per milligram of skin, M,
and of infective (L3) larvae, L, per blackfly vector. A model prototype
(without explicit age structure) was presented by Bas
an ~ez and Boussinesq
(1999) and extended to incorporate host age and sex to account for varying
age- and sex-specific microfilarial profiles in endemic areas of northern
Cameroon, central Guatemala and southern Venezuela (Filipe et al.,
2005). Fig. 2 presents these profiles and the corresponding model fit. The
main blackfly vectors in each of these areas are, respectively, S. damnosum
sensu stricto (s.s.)/S. sirbanum (in African savannah), S. ochraceum s.l.
(in Mesoamerica) and S. guianense s.l. (in the Amazonian focus). For this
chapter we focus on the parameterization of EPIONCHO with data on
human demography, parasitology and entomology of northern Cameroon
(representing areas of Sudan-type savannah in Africa). Detailed equations
are given in Section 2.1.3.1. Table 1 lists state variables and parameters in
EPIONCHO, and provides their definitions, notation, values and sources.
River Blindness 261

Figure 2 Observed and EPIONCHO-predicted age profiles of microfilarial load (mf/mg)

by sex for three different ecological settings at endemic equilibrium. The circles and error
bars are, respectively, the mean and standard error of observed mf/mg within w10-year
age groups (open circles denote women; solid circles denote men) and the lines are the
model fit (to individual) data from (A) northern Cameroon (w5000 individuals); (B) central
Guatemala (w900 individuals) and (C) southern Venezuela (w1000 individuals) (dashed
lines represent women and solid lines represent men) (Filipe et al., 2005).

2.1.1 Parasite population regulation in humans

2.1.1.1 Parasite establishment
Following Dietz (1982), the probability of L3 larvae establishing (and devel-
oping into adult worms) within the human host, dH, is assumed to be
described by a decreasing function of the rate at which L3 larvae are acquired
when the host is bitten (which itself depends on the vector biting rate, m b,
and the mean number of L3 larvae per fly, L), the so-called annual transmis-
sion potential (ATP, No. L3/person/year). The parameters of this (negative)
density-dependent parasite establishment rate were estimated by fitting the
relationship between the (arithmetic) age- and sex-standardized mean
microfilarial load in the community, M, and the ATP (m b L, in yeare1)
measured for each community for a number of villages with associated
parasitological and entomological data, as described in Bas
an ~ez and
Boussinesq (1999) and Bas
an~ez et al. (2002),
Table 1 Definition and values of variables and parameters for EPIONCHO

262
Expression,
average value
Symbol Definition of variables and parameters and units Sources
Parasite in human host
Ns,d(t,a) Mean number of nonfertile female adult worms Eq. (20) Turner et al. (2013a)
per person at time (t) and age (a); subscript s
denotes host sex and d denotes treatment
adherence category
Fs,d(t,a) Mean number of fertile female adult worms per Eq. (21)
person at time (t) and age (a); subscripts s and
d as above
Ms,d(t,a) Mean number of microfilariae (mf ) per Eq. (22)
milligram of skin at time (t) and age (a);
subscripts s and d as above
dH[L(t)] Proportion of L3 larvae developing to adult dH0 þdHN cH mb LðtÞ ~ez and Boussinesq
Bas
an
1þcH mb LðtÞ
worms within the human host as a function of (1999)
the number of infective larvae received per
unit time
d H0 Proportion of L3 larvae developing to adult 0.0712e0.0854 ~ez et al. (2002) and
Bas
an
worms within the human host when Filipe et al. (2005)
mbL(t) / 0
d HN Proportion of L3 larvae developing to adult 0.00299

M.G. Bas
an
worms within the human host when
mbL(t) / N
5.86  103 year per L3 larva

~ez et al.
cH Severity of transmission intensity-dependent
parasite establishment within the human host
p Prepatent period (from infection with L3 larvae 2 year Filipe et al. (2005)
to presence of detectable microfilariae in the
skin)
 River Blindness
mH Per capita death rate of human hosts 0.02 year1
0.04 year1 ~ez and Boussinesq
Bas
an
(1999) and Filipe et al.
(2005)
sW Per capita death rate of adult worms 0.1 year1 Plaisier et al. (1991a)
sM0 Per capita death rate of microfilariae in the 0.8 year1 Duke (1993)
absence of ivermectin
6 Per capita rate at which untreated, 0.59 year1 ~ez et al. (2008)
Bas
an
nonreproducing female worms become fertile
l0 Per capita rate at which untreated fertile female 0.33 year1
worms become nonfertile in the absence of
treatment
ε Per capita rate of production of microfilariae per 1.1538 year1 Turner et al. (2013a)
fertile female worm scaled by the total weight
(in milligrams) of microfilariae-bearing skina
am Maximum recorded human age in the reference 80 year Filipe et al. (2005)
population of northern Cameroon
r(a) Probability density function of host age a (using a mH expðmH a Þ Filipe et al. (2005)
1expðmH am Þ
truncated exponential distribution of survival
times)
hd Proportion of the host population in adherence e Turner et al. (2013a)
group d
qs Proportion of the host population in sex group s qF ¼ 0.45; qM ¼ 0.55 Filipe et al. (2005)
Parasite in simuliid vector
L(t) Mean number of infective larvae per fly Eq. (24) Turner et al. (2013a)
at time (t)

263
m Vector to host ratio 609, for ABR ¼ 19,000 bites For 70% prevalence
person1 year1
(Continued)
Table 1 Definition and values of variables and parameters for EPIONCHOdcont'd

264
Expression,
average value
Symbol Definition of variables and parameters and units Sources
b Biting rate per fly on humans assuming a human 31.2 year1 ~ez and Boussinesq
Bas
an
blood index ¼ 0.3 (1999)
dV 0
dV[Ms,d(t,a)] Proportion of microfilariae developing to the ½1þcV Ms;d ðt;aÞ
infective stage within the vector, per bite

sL[Ms,d(t,a)] Per capita net rate of loss of L3 larvae from aH
þ sL þ mV þ aV Ms;d ðt; aÞ
g
vectors
d V0 Proportion of microfilariae developing to L3 0.0207
within vectors when Ms,d(t,a) / 0, per bite
cV Severity of density-dependent limitation of 0.0148
larval development within (savannah) vectors
aH Proportion of infective, L3 larvae shed per bite 0.54e0.8 Renz (1987) and Duke
(1973)
g Average duration between consecutive blood- 0.0096 year ~ez and Boussinesq
Bas
an
meals (1999)
sL Per capita death rate of L3 larvae within the 52e104 year1
vector
m V0 Per capita death rate of uninfected blackflies 26e52 year1
aV Parasite-induced death rate of infected blackflies 0.597
 year1 per microfilaria ~ez et al. (2002)
Bas
an
0
U s(a) Age- and sex-specific measure of exposure to Es gs E0 ; a < a Filipe et al. (2005)

M.G. Bas
an
0 0
vectors Es gs exp½as ða a Þ; a > a
Es Sex-specific exposure to vector bites EF ¼ 0.90; EM ¼ 1.08
E0 Fraction of exposure at age 0 in relation to that at 0.10; in Cameroon a0 was

~ez et al.
age a’ from which exposure changes with age estimated to be ¼ 0
 River Blindness
gs Normalization factors to ensure that the gF ¼ 0.548; gM ¼ 1.154 Filipe et al. (2005)
distribution of bites among age groups
sums to 1
as Age-specific change in contact rate with vectors aF ¼ 0.023; aM ¼ 0.007 Filipe et al. (2005)
for human hosts of sex s
Mating probability and parasite prevalence
f[Ws,d(t,a), kW] Mating probability at time t, Eq. (25) Turner et al. (2013a)
age a, sex s and treatment adherence group d
Ws,d(t,a) Mean number of female adult worms per person Ns,d(t,a) þ Fs,d(t,a) Turner et al. (2013a)
at time (t) and age (a), s denotes sex and
d denotes treatment adherence category
kW Inverse measure of degree of overdispersion in 0.35 Bottomley et al. (2008)
the distribution of worms among hosts
pd(t) Microfilarial prevalence at time t in adherence Eq. (39) Turner et al. (2013a)
group d
kM[Md(t)] Inverse measure of the degree of overdispersion Eq. (41) Turner et al. (2014a)
in the distribution of skin microfilariae among
hosts of adherence group d, as a function of
the mean microfilarial load
k0 Parameters of the relationship between kM and 0.013 Turner et al. (2014a)
skin microfilarial load
k1 0.025
a
Note that ε is different from ε0 the scaled per capita rate of microfilarial production by a (mated) female worm (regardless of fertility status), whose value is 0.667 year1
~ez and Boussinesq, 1999).
(Bas
an

265
266 ~ez et al.
M.G. Bas
an

ε0 dH ðLÞmbL
M ðmbLÞ ¼ ; (1)
2ðsW þ mH ÞðsM0þ mH Þ
dH0 þ dHN cH mbL
dH ðLÞ ¼ ; (2)
1 þ cH mbL
where m is the vector to human ratio (V/H); b is the biting rate per fly on
humans; L is the average number of infective (L3) larvae per fly; ε0 is the per
capita rate of microfilarial production per (mated) female worm, scaled by
the total weight (in milligrams) of microfilariae-bearing skin; sW is the per
capita mortality rate of adult worms; sM0 the per capita mortality rate of
microfilariae (in the absence of microfilaricidal treatment); mH the per capita
death rate of human hosts; dH0 and dHN are, respectively, the maximum and
minimum establishment probabilities of L3 larvae (L) within humans
(as transmission rate tends to zero or becomes infinitely large), and measures
the severity of transmission rate-dependent constraints upon L3 establish-
ment within humans. Parameter b is the product of multiplying the biting
rate per fly (the reciprocal of the mean duration between two consecutive
blood meals, g, taken as 3.5 days) times the proportion of blood meals taken
on human hosts, h. (i.e., b ¼ h/g). Previous runs of EPIONCHO had
assumed that one-third of the blood meals are of human origin (h ¼ 0.33) in
Cameroon, based on Disney and Boreham (1969), but a more recent and
extensive study of S. damnosum host choice in Ghana (Lamberton et al.,
2012, 2016) indicates that two-thirds of blood meals may be taken on hu-
man hosts by S. damnosum s.s./S. sirbanum (h ¼ 0.67). Also, note that the
estimated value of dHN (0.003) is very similar to the success ratio (sr) of
0.0031 used by ONCHOSIM, as described in Section 2.2.2.2 (Tables 1, 3
and 5).
Other authors (Duerr et al., 2003) have assumed, instead, that the parasite
establishment rate is an increasing (positive density-dependent) function of
the number of adult worms already established, describing a phenomenon
of immunosuppression that would explain profiles of microfilarial load
that increase with host age. In EPIONCHO this phenomenon is explained
by age- (and sex)-dependent exposure to blackfly bites as described in Filipe
et al. (2005). The contact rate per human with vectors is m b Us(a), with m
and b as above and,

Es gs E0 ; a < a0
Us ðaÞ (3)
Es gs exp½ as ða  a Þ; a  a0
0
River Blindness 267

is an age (a)- and sex (s)-specific measure of exposure to vectors with

parameters
P E0, Es and as, and population average equal to 1 (ensured by
Es qs ¼ 1 and factors gs, where qs is the proportion of the population in
s
each sex). Relative exposure (of males with respect to females) is defined by
Q ¼ EM/EF. After an increase in exposure, approximated by a step function
(E0 < 1), during childhood period a0 (Dietz, 1982; Remme et al., 1986),
contacts can increase (as < 0), decrease (as > 0) or remain constant (as ¼ 0)
with age. The value of a0 was estimated to be equal to zero for Cameroon
(Filipe et al., 2005).
2.1.1.2 Mating probability of female adult worms
Following May (1977), the probability that a female worm is mated depends
on: (1) the sex ratio (assumed to be 1:1 in Onchocerca volvulus, Schulz-Key,
1990); (2) the sexual system (assumed to be polygamous, Schulz-Key and
Karam, 1986) and (3) the distribution of adult worms among the human
host population (assuming that males and females are distributed together
following a negative binomial with overdispersion parameter kW, Duerr
et al., 2004). The mating probability, f(W,kW), is an increasing (positive
density-dependent) function of mean female (nonfertile, N plus fertile, F)
worm burden, W ¼ N þ F, whose shape and rate of increase (from 0 to
1) is inversely influenced by the value of kW (the smaller the value, the stron-
ger the degree of parasite overdispersion and the faster the mating probability
increases with mean worm burden) (Anderson and May, 1985),
 
W ðkW þ1Þ
f½W ; kW  ¼ 1  1 þ : (4)
kW

2.1.1.3 Excess human mortality

In addition to excess mortality due to onchocerciasis-associated blindness
(Kirkwood et al., 1983), there is a density-dependent relationship between
microfilarial load and relative risk of mortality (Little et al., 2004b; Walker
et al., 2012b). Some versions of EPIONCHO have incorporated the
relationship between microfilarial load and blindness incidence (Little
et al., 2004a), and between microfilarial load and human excess mortality
(Little et al., 2004b; Walker et al., 2012b) in order to link the core infection
model with a disease model for the estimation of disease burden and cost-
effectiveness of control interventions (Turner et al., 2014a, 2014b). Both
relationships are parameterized using: (1) the microfilarial load lagged by
2 years (reflecting that blindness and excess mortality are associated with
268 ~ez et al.
M.G. Bas
an

past rather than current infection) and (2) the mean number of microfilariae
per skin snip (as opposed to per mg of skin), which is designated M 0
(as opposed to M ) and is derived from the modelled microfilarial load
(per mg of skin) assuming an arithmetic mean skin snip sample weight of
1.7 mg estimated using data from Collins et al. (1992). The relative risk of
blindness associated with infection is given by a simple log-linear function
of M 0 (lagged by 2 years, i.e., M 0 ðt 2Þ, but with the time dependence
omitted for brevity). By contrast, relative risk of mortality associated with
(past) infection is nonlinearly related to M 0 and host age, a, by the expression
exp½ f ðM 0 Þaw  where,
b1 M 0b3
f ðM 0 Þ ¼ ; (5)
ð1 þ b2 M 0b3 Þ
and parameters b ¼ {b1,b2,b3} and w were estimated by fitting to the
longitudinal OCP dataset collected from 1974 through 2001 (Walker et al.,
2012b). Results indicate that for a given microfilarial load the relative risk of
mortality is statistically significantly greater in those aged less than 20 years
(Fig. 3).

Figure 3 Observed and fitted relative mortality risk with Onchocerca volvulus
microfilarial skin load according to age group. Individuals <20 years old (open squares
and solid line, respectively); individuals 20 years old (open circles and dashed line,
respectively). The fitted sigmoid doseeresponse model is adjusted to the average
age of the respective age groups. Shaded (grey) areas around the fitted lines represent
95% Bayesian credible intervals; error bars represent 95% confidence intervals around
observations. Inset permits visual inspection of the mortality relative risk at parasite
loads 40 microfilariae per skin snip (Walker et al., 2012b).
River Blindness 269

2.1.2 Parasite population regulation in vectors

2.1.2.1 Parasite establishment
Following Bas
an ~ez et al. (1994, 1995, 2009) and Soumbey-Alley et al.
(2004), the probability of microfilariae (ingested by the vector) developing
into L3 larvae, dV(M), is a decreasing (negative density-dependent) function
of microfilarial load in African savannah vectors such as S. damnosum s.s./
S. sirbanum. The parameters of this function have been estimated by fitting
the relationship between thoracic microfilariae (L1 uptake) and microfilarial
load, L(M) ¼ dV(M)M, assuming that once established within the thoracic
muscles, L1 larvae will develop to the infective stage, with,
dV0
dV ðM Þ ¼ ; (6)
ð1þ cV M Þ
dV0 M
LðM Þ ¼ ; (7)
1 þ cV M
where dV0 is the initial slope or maximum establishment probability (as
microfilarial load tends to zero), and cV the severity of density-dependent
constraints acting on microfilariae (M). The maximum number of larvae
establishing (as microfilarial load becomes infinitely large) is given by dV0 =cV
and, with the parameter values given in Table 1 (0.0207/0.0148), is equal to
1.4. (In ONCHOSIM, this maximum value is 1.2, as described in Section
2.2.3.1; Tables 3 and 5.)

2.1.2.2 Excess vector mortality

Following Bas
an ~ez et al. (1996, 2009), there is a density-dependent relation-
ship between microfilarial intake (linearly related to skin microfilarial load,
~ez et al., 1994; Demanou et al., 2003) and the rate of vector mortality,
Bas
an
such that the life expectancy of infected flies decreases with the number of
ingested microfilariae. Blackfly mortality as a function of microfilarial load,
mV(M), is given by,
mV ðM Þ ¼ mV0 þ aV M ; (8)
where mV0 is the background per capita mortality rate taken as the reciprocal
of the life expectancy of uninfected flies (Bas
an ~ez et al., 1996) and aV the
excess rate of mortality per microfilaria (Bas
an~ez and Boussinesq, 1999). The
overall per capita rate of loss of infective larvae, sL(M) is, therefore, deter-
mined by their own background death rate, sL, the vector mortality rate,
270 ~ez et al.
M.G. Bas
an

mV(M) and the rate at which L3 larvae are shed when flies bite (on human or
nonhuman blood hosts, aH/g),
sL ðMÞ ¼ sL þ mV0 þ aV M þ ðaH =gÞ; (9)
where aH is the proportion of L3 larvae shed per bite, varying between 0.54
(Renz, 1987) and 0.8 (Duke, 1973) and g the average duration between two
consecutive blood meals, also known as the length of the gonotrophic cycle,
taken as stated above to be 3.5 days (Crosskey, 1990).
The EPIONCHO precursors (Bas
anez and Boussinesq, 1999; Bas
anez
and Ric
ardez-Esquinca, 2001), prior to the introduction of human host
age structure (Filipe et al., 2005), have incorporated the full set of density-
dependent processes described here, with the model used in Bas
an ~ez et al.
(2007) also including the rates of progression through the larval L1, L2,
and L3 stages within the simuliid vector. Age-structured versions such as
Filipe et al. (2005) have subsumed the regulatory processes within the vector
into a single (linearly increasing) relationship between microfilarial load and
excess fly mortality; accordingly, different parameter values have been used.

2.1.3 Pretreatment parasite dynamics

2.1.3.1 Endemic equilibrium situation
Filipe et al. (2005) have presented the EPIONCHO model for the situation
of endemic equilibrium, i.e., assuming that the parasite population is in equi-
librium with respect to time before the inception of control interventions.
This assumption was justified by comparing and confirming stability of
microfilarial prevalence and intensity reported in the 1970s by Anderson
et al. (1974) and in the late 1980s by Boussinesq (Boussinesq, 1991; Bas
an ~ez
and Boussinesq, 1999) in the same area of northern Cameroon. We provide
the equations describing mean numbers of worms with respect to host age
here to facilitate access by readers and to highlight modifications that were
introduced by Turner et al. (2013a),
dNs ðaÞ 1
¼ m b Us ða pÞdH ðL  ÞL  expð mH pÞ þ l0 Fs ðaÞ
da 2
 ð6þ sW ÞNs ðaÞ (10)

dFðaÞs
¼ 6 Ns ðaÞ  ½l0 þ sW Fs ðaÞ; (11)
da
such that adding Eqs (10) and (11) gives the total mean number of adult
female worms (W ¼ N þ F) per host,
River Blindness 271

dWs ðaÞ 1 
¼ m b Us ða pÞdH ðL  Þ L  expð mH pÞ  sW Ws ðaÞ; (12)
da 2
dMs ðaÞ
¼ f½Ws ðaÞ; kW εFs ðaÞ  sM0 Ms ðaÞ; (13)
da
dLs ðaÞ
¼ b Us ðaÞdV ½Ms ðaÞM ðaÞ  sL ½Ms ðaÞLs ðaÞ; (14)
da
X Z

L ¼ qs rðaÞUs ðaÞLs ðaÞda: (15)
s
a

In addition to the parameters described above, ε is the per capita rate of

microfilarial production per fertile female worm scaled by the total weight (in
milligrams) of microfilariae-bearing skin (notice that this parameter is
different from ε0 , defined in Section 2.1.1.1); p is the prepatent period
(the period between infection with infective larvae and microfilariae being
detectable in the skin (Prost, 1980); l0 is the per capita rate at which un-
treated fertile female worms become nonfertile in the absence of treatment;
6 is the per capita rate at which untreated, nonreproducing female worms
become fertile; qs is the proportion of the human population in sex group
(women, men) s and r(a) is the proportion of individuals alive at age a.

2.1.3.2 Transmission seasonality

In some foci, the breeding sites of the simuliid vectors dry up and biting rates
dwindle to zero during the dry months of the year, transmission being
confined to the rainy months when the vectors have repopulated the
breeding sites. This is for instance the case of S. sirbanum in the western exten-
sion of the OCP, potentially decreasing the effectiveness of ivermectin treat-
ment if it is not timed to ensure minimal skin microfilarial levels when biting
rates are highest (Diawara et al., 2009). Some versions of EPIONCHO
(Turner et al., 2015b) have been modified to permit the instantaneous biting
rate of blackfly vectors (the number of bites received per person per unit time)
BR ¼ m b to vary within the year according to a sinusoidal functional that has
been used to model seasonality of malaria transmission (Griffin et al., 2010),
BRðtÞ ¼ X  fc þ ð1 cÞ ½1=2 þ 1=2  cos½2p ðt uÞk g: (16)
Here, X is the instantaneous peak biting rate within the year, c defines the
minimum biting (¼c  X, with (0  c  1), u defines the position of the
transmission peak and k is a shape parameter, with k > 0. In foci with
272 ~ez et al.
M.G. Bas
an

seasonal transmission, the endemic equilibrium conditions given in Section

2.1.3.1 correspond to the annual biting rate (ABR), the instantaneous biting
rate averaged over the year,
Z1
ABR ¼ BRðtÞdt (17)
0

2.1.4 Posttreatment parasite dynamics

2.1.4.1 Ivermectin
In EPIONCHO, the dynamics of skin microfilarial load and of the propor-
tion of adult female worms producing live microfilariae following iver-
mectin treatment with the standard dose of 150 mg/kg are modelled
according to the results of the systematic review, metaanalysis and modelling
presented by Bas
an~ez et al. (2008). Briefly, microfilaridermia is reduced by
half after 24 h, by 85% after 72 h, by 94% after 1 week and by 98%e99%
after 1e2 months (microfilaricidal effect), the latter also corresponding to
the time when the fraction of females harbouring live microfilariae is at its
lowest (embryostatic effect), reduced by around 70% from its original value.
After the first 2 months following treatment, microfilariae gradually reap-
pear in the skin following the resumption of microfilarial production by
the female worms. The microfilaricidal effect (excess mortality of microfilar-
iae due to treatment), sM1 ðsÞ, is modelled as,
sM1 ðsÞ ¼ ðs þ vÞu ; (18)
where s is time after treatment, v is a constant added to time after treatment
to allow for a very large, yet finite, microfilaricidal effect at the point of
treatment and u is a shape parameter for the per capita death rate of
microfilariae following treatment. The embryostatic effect (the treatment-
induced per capita rate at which fertile females become nonfertile), l1(s), is
modelled as,
l1 ðsÞ ¼ lMAX
1 expð4sÞ; (19)
where lMAX
1 is the maximum rate of treatment-induced sterility, and 4 is the
rate of decay of this effect with time after treatment.
At present, EPIONCHO does not assume that standard dose ivermectin
treatment has a direct macrofilaricidal (killing of the adult worms) effect, but
an antimacrofilarial effect (a cumulative reduction in the rate of microfilarial
production by adult females of 7% per dose) has been assumed in more
River Blindness 273

recent versions (Turner et al., 2014c) to account for results presented by

Gardon et al. (2002) and Cupp and Cupp (2005). The modelling of this cu-
mulative, antimacrofilarial effect is described in Section 2.1.5.

2.1.4.2 Moxidectin
The temporal dynamics of skin microfilarial loads from the ivermectin treat-
ment arm in the phase II moxidectin study (Awadzi et al., 2014) were within
the range observed by Bas
an~ez et al. (2008) (Fig. 4A). Moxidectin treatment
was assumed to exert the same types of effects on the parasite as ivermectin.
Therefore, moxidectin’s effects were parameterized by fitting the functions
used by Bas
an~ez et al. (2008) (Eqs (18) and (19) above) to the percentage
reduction in skin microfilarial densities from pretreatment, measured
8 days, 1, 2, 3, 6, 12 and 18 months after a single dose of 8 mg moxidectin
(91e186 mg/kg) (Fig. 4B).

Figure 4 The dynamic effect of a single dose of ivermectin (A) and moxidectin (B) on
skin microfilarial load. The data points are derived from skin microfilarial loads (the
mean of four microfilarial counts) collected from (A) 45 individuals treated with iver-
mectin and (B) 38 individuals treated with moxidectin, as part of the Phase II clinical
safety trial of moxidectin for the treatment of onchocerciasis (Awadzi et al., 2014).
The effect of a single dose of ivermectin previously fitted to microfilarial load data
by Bas
an~ez et al. (2008) is shown as a solid line in (A). The microfilarial dynamics induced
by ivermectin are not re-estimated here and hence provide a validation of the previous
parameterization. The dynamical effect of moxidectin was fitted to the trial data on
microfilarial loads from treated participants using the same approach as in Bas
an ~ez
et al. (2008) and is shown as a solid red line in (B). Error bars are the 95% confidence
intervals which in some circumstances were narrower than the plotted data point
and so are not discernible (Turner et al., 2015b).
274 ~ez et al.
M.G. Bas
an

2.1.4.3 Coverage and adherence

Whilst (therapeutic) coverage describes the proportion of the population
treated at a particular treatment round, adherence (compliance) describes
the degree to which individuals adhere correctly to the treatment schedule.
In EPIONCHO, the human host population (and subsequently the parasite
population) is partitioned into different treatment groups according to how
regularly they receive ivermectin treatment: (1) a fully compliant group who
takes treatment every round; (2) two semicompliant groups who take treat-
ment every other round alternately, and (3) a systematically noncompliant,
fourth, group who never takes treatment.

2.1.4.4 Infection dynamics

The following set of partial differential equations (omitting time and age
dependencies on the left hand side for simplicity) describes the dynamics
of infection intensity in human and vector hosts under treatment with iver-
mectin (or moxidectin), with subscript s denoting host sex and d denoting
treatment adherence category,
vNs;d vNs;d 1
þ ¼ m b Us ða pÞdH ½Lðt pÞLðt pÞexpð mH pÞ
vt va 2 (20)
þ ½l0 þ l1 ðsÞFs;d ðt; aÞ  ð6þ sW ÞNs;d ðt; aÞ

vFs;d vFs;d
þ ¼ 6 Ns;d ðt; aÞ  ½l0 þ l1 ðsÞ þ sW Fs;d ðt; aÞ (21)
vt va
vMs;d vMs;d  
þ ¼ f Ws;d ðt; aÞ; kW εjd ðtÞFs;d ðt; aÞ
vt va (22)
 ½sM0 þ sM1 ðsÞMs;d ðt; aÞ

vLs;d vLs;d    
þ ¼ b Us ðaÞdV Ms;d ðt; aÞ Ms;d ðt; aÞ  sL Ms;d ðt; aÞ Ls;d ðt; aÞ
vt va
(23)
XX Z
LðtÞ ¼ qs hd rðaÞUs ðaÞLs;d ðt; aÞda (24)
s d a
Function l1(s) denotes the excess per capita rate at which fertile females
become nonfertile following treatment (embryostatic effect), with s being
the time since last treatment (Eq. (19) above); f[Ws,d(t,a),kW] the mating
probability as described in Eq. (4) and Section 2.1.4.5; sM1 ðsÞ is the excess
per capita death rate of microfilariae following ivermectin or moxidectin
River Blindness 275

~ez et al., 2008, Eq. (18)), and jd(t)

treatment (microfilaricidal effect, Bas
an
the average value of the factor modifying (decreasing) female worm fertility
in adherence group d when a cumulative effect of treatment is considered
(Section 2.1.5).

2.1.4.5 Mating probability

It is assumed that the distribution of adult worms among hosts of the same
adherence group is adequately described by a negative binomial distribution
(NBD) with mean (female) worm load, Ws,d(t,a), and overdispersion param-
eter, kW. Assuming that: (1) male and female worms are distributed together,
(2) they are polygamous, i.e., a single male has the potential to fertilize all
females within a host (Schulz-Key and Karam, 1986; Hildebrandt et al.,
2012) and (3) they have a balanced (1:1) worm sex ratio, the probability
that a female worm is mated (May (1977) is,
 
  Ws;d ðt; aÞ ðkW þ1Þ
f Ws;d ðt; aÞ; kW ¼ 1  1 þ : (25)
kW
Note that the degree of overdispersion of the adult worm population
(inversely measured by the value of kW) is assumed to be unaffected by
treatment.

2.1.4.6 Cumulative effect of treatment on female worm fertility

At any time after the start of a simulated treatment programme, the worm
population in adherence group d comprises worms previously exposed to
different numbers of ivermectin (or moxidectin) treatments. This is because
(1) worms continually infect hosts throughout the treatment programme
and (2) hosts in different adherence groups receive different numbers of treat-
ments at different times. If ivermectin or moxidectin are assumed to suppress
cumulatively the fertility of female O. volvulus, then the average reduction in
fertility of the worm population will critically depend on the fraction of
worms exposed to different numbers of treatments. To this end, n was defined
as the maximum number of previous exposures to ivermectin, and n þ 1 sub-
models were formulated to track worm populations acquired during discrete
time intervals throughout the course of a simulated treatment programme.
Note that n varies among adherence groups (for example, for systematic non-
compliers n ¼ 0), and exposure group (number of treatments to which
worms have been exposed, j), as some worms, acquired after the final treat-
ment, will be unexposed to treatment ( j ¼ 0). (The possibility of unexposed
worms gives rise to the n þ 1 (as opposed to n) submodels.)
276 ~ez et al.
M.G. Bas
an

Consider a treatment programme starting at time s0 (that is, the first dose
of ivermectin or moxidectin is administered at time t ¼ s0 ). Worms exposed
to all n treatments ( j ¼ n) are those that were acquired at time t < s0 . By
redefining the rate of establishment of female adult worms as (first term of
the right hand side of Eq. (20)),
1
Ls ðt; aÞ ¼ m b Us ða pÞdH ½Lðt pÞLðt pÞexpð mH pÞ; (26)
2
the rate of establishment of adult female worms that will be exposed to all n
treatments (i.e., those acquired before the commencement of treatment) in
adherence group d can be expressed as,

Ls ðt; aÞ for 0 < t < s0
Ls;d;j¼n ðt; aÞ ¼ (27)
0 otherwise:
By contrast, unexposed female worms ( j ¼ 0) are those acquired after
the last treatment which, if the n treatments were administered at frequency
f (where f ¼ 1 represents annual treatment and f ¼ 2 represents biannual
treatment), indicates that infection occurred at t > s0 þ (n  1)/f. (In this
chapter we explore an annual (ivermectin, moxidectin) or a 6-monthly
(ivermectin) treatment frequency.) That is,

Ls ðt; aÞ for s0 þ ðn  1Þ=f < t < N
Ls;d;j¼0 ðt; aÞ ¼ : (28)
0 otherwise:
It follows that the rate of establishment of adult worms exposed to the
intervening numbers of treatments j ¼ 1, 2,., n  1 is given by,

Ls ðt; aÞ for s0 þ ðn  1  jÞ=f < t < s0 þ ðn  jÞ=f
Ls;d;j¼0 ðt; aÞ ¼
0 otherwise:
(29)
These conditions are used to define partial differential equations for the
mean number of female adult worms, Ws,d,j(t, a), in each exposure group
j ¼ 0, 1,., n,
vWs;d;j ðt; aÞ vWs;d;j ðt; aÞ
þ ¼ Ls;d;j ðt; aÞ  sW Ws;d;j ðt; aÞ: (30)
vt va
Note that for the purposes of tracking adult worms exposed to different
numbers of treatments, the fertility status (fertile/nonfertile) of female
worms is not distinguished. Taking the expectation of Ws,d,j(t,a) with respect
to host age a and sex s yields,
River Blindness 277

X Z
Ws;d ðtÞ ¼ q rðaÞWs;d;j ðt; aÞda;
s s
(31)
a

where r(a), the probability density function of host age, a, is

mH expðmH aÞ
rðaÞ ¼ : (32)
1  expðmH am Þ
Summing over treatment exposure groups gives the mean number of
worms per host in adherence group d,
X
j¼n
Wd ðtÞ ¼ Wd;j ðtÞ: (33)
j¼0

The fraction of the total female worm population in treatment exposure

group j, denoted ud,j(t), is now given by,
Wd;j ðtÞ
ud;j ðtÞ ¼ : (34)
Wd ðtÞ
Each subsequent exposure to ivermectin or moxidectin (after the first
exposure) was assumed to cause a 7% reduction in female worm fertility
(varied in the sensitivity analysis between 1% e weak cumulative effect e
and 30% e strong cumulative effect), such that the fertility of female worms
exposed to j treatments, Jj, is given by,

1 for j ¼ 0
Jj ¼ (35)
ð1  zÞj1 for j > 0
with parameter z ¼ 0.01 (minimum value), 0.07 (nominal value) or 0.3
(maximum value) (Table 2). The maximum value was motivated by the
findings of the modelling study conducted by Plaisier et al. (1995),
fitting to data from Alley et al. (1994) on the first community trial of
annual ivermectin treatment in the then highly hyperendemic focus of
Asubende in Ghana using ONCHOSIM. Note that for j ¼ 0 (and for
j ¼ 1), Jj ¼ 1 indicates that EPIONCHO assumes that worms previously
unexposed to treatment ( j ¼ 0), or exposed to a single, first dose ( j ¼ 1)
have, respectively, full fertility, or the potential to regain full fertility.
Subsequent treatments may cause a cumulative reduction of female worm
fertility.
The average value of the factor modifying the per capita microfilarial
production rate of (fertile) female worms in adherence group d, jd(t), is
Table 2 Definition and values of parameters and variables for ivermectin or moxidectin treatment effects in EPIONCHO

278
Symbol Definition of variables and parameters Expression, average value and units Sources

n Maximum number of previous 0 for those hosts never taking treatment to Turner et al. (2013a)
exposures to ivermectin by worms in 15 (annual) or 30 (biannual) for those
a given adherence group taking all treatments
f Frequency of treatment Ivermectin: Annual or biannual Turner et al. (2013a)
Moxidectin: Annual
s Time since last ivermectin (or years e
moxidectin) treatment
l1(s) Excess per capita rate at which fertile lMAX
1 expð4 sÞ year1 ~ez et al. (2008)
Bas
an
females become non-fertile
following treatment (embryostatic
effect)
lMAX
1 Maximum rate of treatment-induced Ivermectin: 32.4 year1 Turner et al. (2015b)
sterility Moxidectin: 462 year1
4 Rate of decay of treatment-induced Ivermectin: 19.6 year1 Turner et al. (2015b)
sterility with time after treatment Moxidectin: 4.83 year1
sM1 ðsÞ Excess per capita death rate of (s þ n)u year1 ~ez et al. (2008)
Bas
an
microfilariae following ivermectin
treatment (microfilaricidal effect)
n Constant added to time after treatment Ivermectin: 0.0096 years Turner et al. (2015b)
to allow for a very large, yet finite, Moxidectin: 0.04 years
microfilaricidal effect at the point of

M.G. Bas
an
treatment
u Shape parameter for the per capita Ivermectin: 1.25 Turner et al. (2015b)
death rate of microfilariae following Moxidectin: 1.82

~ez et al.
treatment
 River Blindness
s0 Time at which treatment programme e e
starts
Ls,d,j(t,a) The rate of establishment of female Eqs (27)e(29) Turner et al. (2013a)
adult worms at time t in hosts of age
a, sex s, treatment adherence group
d and exposure group (number of
treatments to which worms have
been exposed) j
Ws,d,j(t,a) Mean number of female adult worms at Eqs (30) and (31) Turner et al. (2013a)
time (t) in hosts of age (a); sex s,
treatment adherence group d and
treatment exposure group j
ud,j(t) The fraction of the total worm Eq. (34) Turner et al. (2013a)
population in treatment exposure
group j
Jj The fertility of adult worms in Eq. (35) Turner et al. (2013a)
treatment exposure group j
z The per dose reduction in fertility 0.01, 0.07, 0.30 Turner et al. (2015b)
caused by treatment when a
cumulative effect is assumed
jd(t) The average value of the factor Eq. (36) Turner et al. (2013a)
modifying female worm fertility in
adherence group d

279
280 ~ez et al.
M.G. Bas
an

calculated using the fraction of the total worm population in each treatment
exposure group ud,j(t) (Eq. (32)) and Jj (Eq. (33)),
X
j¼n
jd ðtÞ ¼ Jj ud;j ðtÞ: (36)
j¼0

Definitions and values of parameters for treatment effects in EPION-

CHO are given in Table 2.

2.1.5 Model outputs

2.1.5.1 Intensity of infection
In this chapter infection intensity refers to microfilarial load in those aged
20 years (to facilitate comparison with ONCHOSIM results, which use
the community microfilarial load [CMFL]). However, CMFL (Remme
et al., 1986) refers to a geometric mean microfilarial load per skin snip in
those aged 20 years, rather than to an arithmetic mean microfilarial load
per mg of skin, as used in EPIONCHO. Microfilarial load in those aged
20 years is calculated from Eq. (22) above by integrating over age (from
a ¼ 20 to a ¼ am, the maximum human age of 80 years recorded in the
Cameroonian datasets) and summing over sex s and adherence group d,

XX Z m
a¼a

M ðtÞ20 ¼ qs hd r0ðaÞMs;d ðt; aÞda; (37)

s d
a¼20

where r0 (a)
is the probability density function of host age between 20 and
am ¼ 80 years,
mH expð mH aÞ
r0 ðaÞ ¼ ; (38)
½expð mH 20Þ  expðmH am Þ
and mH is the per capita death rate of humans.

2.1.5.2 Prevalence of infection

According to the current version of EPIONCHO, overall microfilarial
prevalence in adherence group d (pd(t)) is derived by using a relationship
between prevalence and microfilarial load at the community level in
Cameroon described in Bas
an ~ez and Boussinesq (1999) and reparameterized
by Turner et al. (2014a). This relationship assumes that skin microfilarial load
per person is distributed according to an NBD with mean Md(t) and
overdispersion parameter kM. The best fit to the microfilarial prevalence
River Blindness 281

vs. intensity relationship was obtained when kM was allowed to be a function

of the mean. Assuming that the degree of microfilarial overdispersion does
not depend on adherence group, pd(t) is given by,
 kM ½Md ðtÞ
Md ðtÞ
pd ðtÞ ¼ 1  1 þ (39)
kM ½Md ðtÞ
where Md(t) is given by,
X Z
Md ðtÞ ¼ qs rðaÞMs;d ðt; aÞda; (40)
s
a

and kM is given by,

k0 Md ðtÞ
kM ½Md ðtÞ ¼ : (41)
1 þ k1 Md ðtÞ
The overall population prevalence at time t was obtained by summing
pd(t) across adherence groups,
X
pðtÞ ¼ hd pd ðtÞ: (42)
d

2.2 ONCHOSIM
ONCHOSIM is a stochastic, individual-based model for the transmission
and control of onchocerciasis. This model describes a dynamic human pop-
ulation, consisting of a discrete number of individuals. The computer pro-
gram tracks change in the composition of the human population and in
the infection status of each individual in the population over time (t, in 1-
month time steps) and age (a). The transmission of infection between indi-
viduals is captured by a deterministic submodel, accounting for the Simulium
fly population dynamics and the fate of the parasite in the fly. The model was
developed in close collaboration with the OCP (Plaisier et al., 1990). A
formal description of the model, presented previously by Habbema et al.
(1996a) and Coffeng et al. (2014a), is included here to facilitate access to
the readers and to allow a direct comparison with EPIONCHO. Table 3 lists
ONCHOSIM’s parameters, notation, values and sources.

2.2.1 Human population demography

The human population dynamics is governed by birth and death processes.
We define F(a) as the probability to survive to age a (apart from excess
282 ~ez et al.
M.G. Bas
an

mortality due to onchocerciasis-associated blindness). The values used are as

follows:

age (a) 0 5 10 15 20 30 50 90
F(a) 1.000 0.804 0.772 0.760 0.740 0.686 0.509 0.000

Survival at intermediate ages is obtained by linear interpolation.

The expected number of births (per year) at a given moment t is
given by,
X
na
Rb ðtÞ ¼ Nf ðk; tÞ$rb ðkÞ; (43)
k¼1

where Nf (k,t) is the no. of women in age group k at time t, rb(k) is the annual
birth rate in age-group k: 0.109 babies per year for women between 15 and
20 years; 0.300 between 20 and 30 years; 0.119 between 30 and 50 years;
0.0 for all other ages and na is the number of age groups considered.
Each month, Rb(t) is adapted according to the number of women and
their age-distribution. Depending on the size of the initial population and
birth and death rates, the human population may increase. The program
allows the specification of a ‘maximum population size’, in order to keep
the size population representative for the type of community being simu-
lated and limit computation time. As soon as the simulated population ex-
ceeds this maximum, a random fraction of the population is sampled and
removed from the population. This can be thought of as emigration. In
most published model applications, the model is used to simulate a village
population with a maximum size of 440. This value is well within the ranges
(23e828, with a median of 171), recorded in the OCP database (O’Hanlon
et al., 2016). The population distribution resulting from the aforementioned
parameters closely follows the age distribution in Sub-Saharan Africa as
shown elsewhere (Coffeng et al., 2014a).

2.2.2 Parasite population regulation in humans

2.2.2.1 Exposure to fly bites
The number of bites mbri(t) a person i gets in month t (in the absence of vec-
tor control) is given by,
mbri ðtÞ ¼ MbrðtÞ Exi (44)
River Blindness 283

where Mbr(t) is the number of bites in month t (Jan., Feb., .) for a person
with relative exposure equal to 1. The relative exposure Exi is calculated as,
Exi ¼ Exaðai ; si Þ$Exii ; (45)
where Exa(ai,si) is the relative exposure of a person of age a and sex s,
assumed to be zero at birth, to increase linearly with age between the ages of
0 and 20 years until a maximum of 1.0 for men and 0.7 for women, and to
remain constant from 20 years onwards, and,
Exii w Gamma(1.0,aExi) is the exposure index of person i. Exii is
assumed to follow a gamma distribution with mean 1.0 and shape and
rate equal to aExi. The exposure index of a person remains constant
throughout their lifetime. For selected West African villages (within
the OCP), estimated aExi values vary between 1.6 and 12.7 (for the sim-
ulations illustrated in this chapter values were 1.0 or 3.5; see Table 3 and
Coffeng et al., 2014a).
Mbr(t) values were obtained from six years of blackfly collections near the
village of Asubende (Ghana) conducted between 1978 and 1985. In this site
with perennial transmission, monthly biting rates of, on average, 2570 bites
per person, varying from 1500 in March to 3750 in November had been
found. For the actual biting rates (Mbr(t)) inside the village Asubende, these
figures were multiplied by a factor (called the relative biting rate) of 0.95.
(Since we have no measurements of biting rates actually experienced by vil-
lagers, we have arbitrarily defined a relative biting rate of 1.0, i.e., a mean
Mbr ¼ 2750 as the biting rate that results in a geometric mean number of
microfilariae (mf) per skin snip (ss) of 100 in a hypothetical village where
all its inhabitants are permanently characterized by a relative exposure of
1.0.) Assuming the same seasonal pattern for other villages, relative biting
rates have been estimated to vary from 0.4 to 0.9.

2.2.2.2 Parasite establishment

The monthly transmission potential (MTP) in ONCHOSIM is defined as
mbr(t)  lr(t). When accumulated over a year, we get the ATP. If during a
blood meal by a simuliid fly in month t, lr infective larvae are released on
average, the force-of-infection foii(t), defined as the expected number of
new adult parasites acquired by person i in month t, is calculated as,
foii ðtÞ ¼ mbri ðtÞ lrðtÞ sr; (46)
where sr is the success ratio, namely, the fraction of inoculated L3 larvae
succeeding in developing to adult male or female worms, with value
284 ~ez et al.
M.G. Bas
an

sr ¼ 0.0031. An average male:female sex ratio of 1:1 is assumed (Schulz-

Key, 1990).
In month t, a person i is assumed to become infected according to a Pois-
son process with rate foii(t). ONCHOSIM assumes that there is no density
dependence in this process.

2.2.2.3 Mating probability of female adult worms

Chance processes determine the number of male and female worms present
in each human individual. The degree of parasite overdispersion in the hu-
man population depends on exposure heterogeneity assumptions. The
reproductive lifespan of male and female parasites is a random variable,
Tl w Weibull(muTl,aTl), with mean muTl ¼ 10 years and shape aTl ¼ 3.8.
(For readers used to other commonly used parameterizations of the Weibull
distribution in terms of shape k and scale l, shape k is aTl (as described in this
document) and scale is l ¼ muTl/G(1 þ 1/aTl).) The microfilarial produc-
tivity r(a,t) of a female worm of age a in month t is calculated as,
rða; tÞ ¼ RðaÞ fmðtÞ; (47)
where
R(a) is the potential microfilarial productivity of a female worm of age a
(in years):
R(a) ¼ 0 for 0  a < 1;
R(a) ¼ 1 for 1  a < 6;
R(a) ¼ 1  ((a  6)/15) for 6  a < 21;
R(a) ¼ 0 for a > 21 and
fm(t) mating factor at time t.
Quantifying R(a) ¼ 0 for 0  a < 1 is equivalent to assuming an intrinsic
latency period (i.e., the time needed for a parasite to become mature and be
able to reproduce) of exactly 1 year for all male and female worms. This
duration is user-specified in ONCHOSIM; other values can be given and
it can also be specified as a continuous probability distribution. Similarly
other values can be specified for the potential microfilarial production by
female worms once the intrinsic latency period has elapsed. However, the
intrinsic latency period is not necessarily equal to the prepatent period, as
the latter is defined as the time from the moment of infection until patency
(microfilarial infection) can be detected in the skin.
The mating factor is defined as follows. To continue microfilarial
production, a female worm must be inseminated each rc months (rc ¼ repro-
ductive cycle ¼ 3 per year). If insemination takes place less than rc months
River Blindness 285

ago, then fm(t) ¼ 1. Otherwise, the probability of insemination or reinsemi-

nation Pins(t) in month t is given by,

Pins ðtÞ ¼ Wm ðtÞ Wf ðtÞ if Wm < Wf

; (48)
Pins ðtÞ ¼ 1 if otherwise
where W(t) is the number of male (Wm) or female (Wf) parasites in the human
host at time t. If no insemination takes place then fm(t) ¼ 0 and the female
worm has a new opportunity in month t þ 1. If insemination occurs in
month ti then fm(t) ¼ 1 during ti  t < ti þ rc. In ONCHOSIM there is one
additional parameter influencing the mating probability Pins. This parameter is
called male potential and is multiplied with the male:female worm sex ratio.
Assigning a high value to this male potential (e.g., 100) implies that mating (if
required) will always take place if there is at least one adult male worm.
The skin microfilarial density sl(t) at time t is calculated by accumulating
the microfilarial production of all female parasites over the past Tm months,
slðtÞ ¼ cw$elðtÞ; (49)

1 Xni X
Tm  
elðtÞ ¼ rj aj  x; t  x ; (50)
Tm j¼1 x¼1

where
rj(aj,t) is the microfilarial productivity of a female worm j of age aj in
month t
el(t) is the effective parasite load at time t. This intermediate variable can be
interpreted as the total number of female worms that have contributed to
skin microfilarial counts at time t, weighted for their average microfilarial
productivity over the past Tm months,
cw is the average contribution of an inseminated female worm at peak
fecundity (R ¼ 1) to the skin microfilarial density: cw ¼ 7.6 microfilar-
iae/worm. (Instead of a linear relationship between sl and el, other func-
tional relationships can be chosen, e.g., a saturating function.)
Tm is the (fixed) microfilarial lifespan, with an assumed value
Tm ¼ 9 months (Plaisier et al., 1995), and
ni is the number of parasites alive during at least one of the months
t  1,.,t  Tm.

2.2.2.4 Microfilarial counts in skin snips

The expected number of microfilariae in a skin snip (of 2 mg) is given by,

cw Xni X
Tm  
ssðtÞ ¼ dj rj aj  x; t  x ; (51)
Tm j¼1 x¼1
286 ~ez et al.
M.G. Bas
an

where, dj is the dispersal factor of female parasite j. This is a random variable

drawn for every ‘newborn’ worm and accounts for differences in the
contribution of female worms to the microfilarial density at the standard site
of the body where snips are taken (hips in Africa). We assume that dj follows
an exponential distribution, dj w Expo(1.0).
The actual (observed) number of microfilariae per skin snip (mf/ss) at
examination time t, ssobs(t) follows a Poisson distribution, ssobs(t) w Pois-
son(ss(t)) e although other discrete probability functions (e.g., geometric)
can be used. At each epidemiological survey two snips (or any other number
as appropriate) are taken from all simulated persons. The results of such a sur-
vey are postprocessed to arrive at age- and sex-specific and standardized
microfilarial prevalences.

2.2.2.5 Blindness and excess human mortality

The event of a person going blind at age a (in months) depends on the
cumulative parasite load (elc) of a person,
X
a
elcðaÞ ¼ elðxÞ: (52)
x¼0

Each person has a threshold level elc (denoted as Elc) at which a person
goes blind. Elc follows a Weibull probability distribution,
Elc w Weibull(muElc,aElc), with mean muElc ¼ 10,000 and shape aElc ¼ 2.0.
Person i goes blind at age a when,
elci ðaÞ  Elci > elci ða  1Þ: (53)
At that moment the remaining lifespan at age a is reduced by a factor rl,
which follows a uniform distribution on [0,1] (hence on average rl ¼ 0.5).
(Any other probability distribution defined on [0,1] can be used, e.g., a
beta distribution.)

2.2.3 Parasite population regulation in vectors

2.2.3.1 Parasite establishment
On the basis of fly-feeding experiments conducted in the OCP (analyzed by
~ez et al., 1995 and summarized by Soumbey-Alley et al., 2004), the
Bas
an
following expression for the relation between L1 uptake (lu) and skin micro-
filarial density in humans (sl) was derived by Plaisier et al. (1991b),
   
lu ¼ a$ 1 eb$sl $ 1þ ec$sl ; (54)
with a ¼ 1.2, b ¼ 0.0213 and c ¼ 0.0861 (the initial slope of this relationship
equals 2ab and, therefore, the maximum probability of parasite establishment
is 0.0511 per microfilaria in a skin snip; the maximum number of larvae
River Blindness 287

establishing within the thoracic muscles of the fly is 1.2). Other functional

relationships can also be defined. For instance, we can set c ¼ 1.0 to simulate a
situation with less pronounced negative density dependence in transmission
(which may be reflective of the situation in forest areas). This alternative
parameter value results in a less concave shape of the function, while the slope
in the origin (which equals 2 ab) and the final saturation level (a) remain the
same. In terms of L1 uptake, this means that uptake is up to 40% lower for
skin microfilarial densities <10 mf/ss, and nearly unchanged for skin mf
densities >40 mf/ss. Increases in c beyond 1.0 do not affect the shape of the
function by much. The choice of setting the value c ¼ 1.0 was arbitrary and
does not necessarily represent forest vectoreparasite complexes.
The mean L1 uptake in the blackfly population per fly bite in month t is
calculated as,
, NðtÞ
X
NðtÞ X
luðtÞ ¼ ðExi lui Þ Exi ; (55)
i¼1 i¼1

where N(t) is the number of persons bitten in month t.

It is assumed that a fixed proportion of the L1 (thoracic) larvae will
develop to the L3 stage and be released during subsequent bites,
lrðtÞ ¼ n luðtÞ; (56)
where
lr(t) is the mean number of L3 larvae released per bite in month t and
v is the transmission probability from vector to humans, defined as the
average probability that an L1 larva completes the extrinsic incubation
period within the blackfly vector and is released as an infective, L3 larva.
In calculating v we take into account the life history of the fly starting
from her first blood meal. We assume that blood meals are taken at fixed
hours during daytime, so that we can use 1 day time steps. Although we
take into account differences in the length of the gonotrophic cycle between
flies (the cycle may take between 2 and 5 days with a mean of 3.5 days), in
the model we assume that a particular fly always has the same cycle length
(which equals the time between two successive blood meals). We further
explicitly account for variation in the duration of development from L1
to L3 (which is mainly determined by environmental temperature; Cheke
et al., 2015). The basic assumption underlying the use of a fixed proportion
v is that at any moment the fly population has a stable age distribution and
that the number of bites per person is large enough to disregard the age of
the biting flies.
288 ~ez et al.
M.G. Bas
an

2.2.3.2 Transmission probability

For the current version of ONCHOSIM, transmission probability v has to
be calculated outside the model and given as a parameter. This section de-
scribes the necessary calculations.
Assume that a fly engorges one L1 larva (microfilariae are essentially L1
larvae as there is no moult between the microfilarial and the L1 stage) at her
mth blood meal, then the probability to release an L3 larva n blood meals
later is given by,
Prel ðnji; j; mÞ ¼ PL1/L3 $ð1 PL3/ Þi $PL3/L3
i
$PL3/ $Sðm; n$jÞ; (57)
where
Prel(nji,j,m) is the probability to release one L3 larva at the (m þ n)th
blood meal if one L1 larva has been ingested during the mth blood
meal, given that
• a gonotrophic cycle takes j days,
• between blood meals m and m þ n there have been i potentially
infective blood meals (i.e., blood meals at which the L1 larvae
have already developed to the L3 stage),
PL1/L3 is the probability that an L1 larva develops to the L3 stage, given
survival of the fly, with PL1/L3 ¼ 0.85 (Collins et al., 1977),
PL3/L3 is the probability that an L3 larva, which is not released at a given
blood meal survives to a next blood meal, given survival of the fly:
PL3/L3 ¼ 0.90,
PL3/ is the probability that an L3 larva is released at a blood meal:
PL3/ ¼ 0.65 (Duke, 1973; Renz, 1987), and
S(m,t) is the probability that a fly survives for t days until blood meal m.
In order to arrive at a general solution for all possible values of i, we use
the probability distribution of the number of potentially infective blood
meals since the meal during which microfilariae (L1 larvae) were ingested
and before the blood meal during which the infective L3 larvae are
released,
X
n1
Prel ðnjj; mÞ ¼ ½Prel ðnji; j; mÞ$Pib ðijn; jÞ; (58)
i¼0

Pib ðijn; jÞ ¼ FdL1/L3 ðjðn  iÞÞ  FdL1/L3 ðjðn  i  1ÞÞ; (59)

where
Pib(ijn,j) is the probability that before the nth blood meal since microfi-
larial intake, i blood meals have been potentially infective (L1 has
become L3), given a cycle length of j days, and
River Blindness 289

FdL1/L3(t) is the probability that the duration of development of L1 to

L3 is equal to or less than t days (FdL1/L3(t) ¼ 0.0 for t  5; 0.07 for
t ¼ 6; 0.86 for t ¼ 7; 1.0 for t  8 days).
A general solution for all possible values of m can be obtained by incor-
porating the probability that a fly takes her mth blood meal,
X
mmax
Prel ðnjjÞ ¼ ½Prel ðnjj; mÞ$Pb ðmjjÞ; (60)
m¼1
,
X
mmax
Pb ðmjjÞ ¼ Lðjðm  1ÞÞ ðjðm  1ÞÞ; (61)
m¼1

where
Pb(mjj) is the probability that a feeding fly takes her mth blood meal at a
cycle length of j days and
L(t) is the probability that a fly lives for at least t days. At present we
assume an age- (and microfilarial load)-independent daily survival of
0.78. This is in rough agreement with a probability of daily survival of
0.81 at 25 C for S. damnosum s.s (Cheke et al., 2015).
Generalizing for j can be achieved by summation, weighted by the prob-
ability distribution of the duration of the gonotrophic cycle,
X
jmax
 
PðnÞ ¼ Prel ðnjjÞ$Pgc ðjÞ ; (62)
j¼jmin

where Pgc( j) is the probability that a gonotrophic cycle takes j days (i.e., j
days between successive blood meals; Pgc( j) ¼ 0.0 for j  2; 0.2 for j ¼ 3;
0.6 for j ¼ 4; 0.2 for j ¼ 5; 0.0 for j  6 days).
Using the following equality,
Sðm; n$jÞ ¼ Lðjðmþ n  1ÞÞ=Lðjðm 1ÞÞ; (63)
the average probability that an L1 larva taken from a human will develop to
the L3 stage and be released to another human is given by,
Prel ¼ PL1/L3 $PL3/ $
8 " # ( 9
> X
mmax
1 X
nmax X
n1
i >
>
> P ðjÞ$ P Lðjðm þ n  1ÞÞ$ ½ð1  P Þ$P  >
>
>
> gc m $ L3/ L3/L3 $ >
>
> m¼1 Lðjðm  1ÞÞ >
max
> >
max < =
m¼1 n¼1 i¼0
jP
:
>
j¼jmin > ) >
>
>
> >
>
> P
> n1 >
>
>
: ½ð1  PL3/ Þ$PL3/L3 i $½FdL1/L3 ðjðn  iÞÞ  FdL1/L3 ðjðn  i  1ÞÞ >
;
i¼0

(64)
290 ~ez et al.
M.G. Bas
an

In Eqs (58)e(61)
amax
mmax ¼ þ 1; truncated to integer
j
; (65)
amax  ðm$jÞ
nmax ¼ þ 1; truncated to integer
j
where amax is the maximum attainable age of the fly (i.e., age at which L(T)
approaches zero).
The transmission probability from vectors to humans v is now given by,
v ¼ Prel $ð1  zÞ; (66)
where z is the fraction of fly bites taken on nonhuman blood host (zoo-
phagy). This value is highly dependent on local circumstances (e.g., human
and nonhuman blood host density, blackfly density and blackfly species
(Lamberton et al., 2016). In ONCHOSIM the value used is z ¼ 0.04,
meaning that 96% of the blood meals are assumed to be taken on human
hosts. This is close to the zoophagy index, z ¼ 0.08 recorded in the Beffa
form of S. soubrense, in Ghana (Lamberton et al., 2016).
Using the indicated quantifications, we have calculated a value for v of
0.073 released infective L3 larvae per L1 larva resulting from a given micro-
filarial uptake. Note that Eq (64) reduces to a much simpler form if we
assume that each day a fraction S of the flies survive, that the gonotrophic
cycle has a fixed duration of dgc days and that the number of blood meals
needed to complete the development of L1 to L3 is fixed to n1 / 3,
S nl/3$dgc
Prel ¼ PL1/L3 $PL3/ $ (67)
1  S dgc $ð1  PL3/ Þ$PL3/L3

2.2.3.3 Excess vector mortality

Excess mortality of infected flies is not considered in ONCHOSIM.

2.3 Comparison between EPIONCHO and ONCHOSIM

The EPIONCHO and ONCHOSIM models were developed indepen-
dently by research teams (respectively based at Imperial College London,
London, and Erasmus Medical Center, Rotterdam) using distinct modelling
approaches, on the basis of diverse datasets and with different initial pur-
poses. EPIONCHO was built following the modelling tradition and
methodology of Anderson and May (1982, 1985, 1991), and Dietz (1976,
1982) for infectious diseases in general and helminthic infections in
Table 3 Definition and values of variables and parameters for ONCHOSIM

River Blindness
Parameter Values and Units Sources
Human demography
Human life table, F(a) See Section 2.2.1 Human population United Nations (2013)
demography
Human fertility, R(t) See Section 2.2.1 Human population United Nations (2013)
demography
Exposure to simuliid vectors
Interindividual variation in exposure to Gamma distribution with mean 1.0 and Plaisier (1996); unpublished OCP data
fly bites (Exi) shape and rate equal to 1.0 or 3.5
Variation in exposure to fly bites by age Eq. (45) Plaisier (1996)
and sex (Exa)
Seasonal variation in exposure to fly 104%, 91%, 58%, 75%, 75%, 66%, 102%, Alley et al. (1994)
bites (mbr) 133%, 117%, 128%, 146%, and 105%
times the average monthly biting rate
(JanuaryeDecember)
Life history and microfilarial productivity of the parasite in the human host
Worm longevity (Tl ) Weibull distribution with mean 10 and Plaisier et al. (1991a)
shape 3.8 (year)
Pre-patent period 1 year Duke (1980) and Prost (1980)
Age (a)-dependent potential R(a) ¼ 0 for 0  a < 1 year Albiez (1985) and Karam et al. (1987)
microfilarial production, R(a) R(a) ¼ 1 for 1  a < 6 years
R(a) ¼ 1  ((a  6)/15) for
6  a < 21 years
R(a) ¼ 0 for a > 21 years

291
(Continued)
Table 3 Definition and values of variables and parameters for ONCHOSIMdcont'd

292
Parameter Values and Units Sources
Longevity of microfilariae (Tm) 9 months Plaisier et al. (1995)
Worm contribution to the skin 7.6 mf/worm Plaisier (1996)
microfilarial load (cw)
Variability in microfilariae per skin snip Poisson distribution with mean ss(t), Habbema et al. (1996a)
(2 mg) Eq. (51)
Dispersal factor for worm contribution Exponential distribution with mean 1 Habbema et al. (1996a)
to skin snip (d )
Mating cycle (rc) 3 months Schulz-Key (1990) and Schulz-Key
and Karam (1986)
Male potential 100 female worms Habbema et al. (1996a)
Vision loss
Blindness threshold (Elc) Weibull distribution with mean 10,000 Coffeng et al. (2013a)
and shape 2.0
Reduction in remaining life 50% Coffeng et al. (2013a), Kirkwood et al.
expectancy due to blindness (1983) and Plaisier et al. (1990)
Parasite in simuliid vector
Fly survival, L(t) 0.78 day1 Habbema et al. (1996a) and Cheke
et al. (2015)
Probability of gonotrophic cycle Pgc( j ) ¼ 0.0 for j  2 days Habbema et al. (1996a); expert opinion

M.G. Bas
an
duration, Pgc( j ) Pgc( j ) ¼ 0.2 for j ¼ 3 days (OCP entomologists)
Pgc( j ) ¼ 0.6 for j ¼ 4 days
Pgc( j ) ¼ 0.2 for j ¼ 5 days

~ez et al.
Pgc( j ) ¼ 0.0 for j  6 days

Zoophagy index, proportion of blood
meals taken on nonhumans blood
hosts (z)
Microfilarial uptake, lu
Probability of duration of larval
development (from L1 to L3),
FdL1/L3(t)
Larval survival (L1 / L3)
L3 survival (L3 / L3)
Larval release (L3)
Success ratio (sr)
Mass treatment coverage and adherence
Coverage, Cw
Age- and sex-specific adherence cr(k,s)
Individual adherence index (co)
Ivermectin
Microfilaricidal efficacy (assumption
sets 1 and 2)
Assumption set 1
Relative effectiveness (v)
River Blindness
0.04 Habbema et al. (1996a); expert opinion
(OCP entomologists)
Eq. (54); a ¼ 1.2, b ¼ 0.0213, and Plaisier et al. (1991b)
c ¼ 0.0861 (main analysis); a ¼ 1.2,
b ¼ 0.0213, and c ¼ 1.0 (sensitivity
analysis)
FdL1/L3(t) ¼ 0 for t  5 days Habbema et al. (1996a); expert opinion
FdL1/L3(t) ¼ 0.07 for t ¼ 6 days (OCP entomologists)
FdL1/L3(t) ¼ 0.86 for t ¼ 7 days
FdL1/L3(t) ¼ 1.0 for t  8 days
0.85
0.90
0.65
0.0031 Plaisier et al. (1996)
User-defined
See page s13 of Supplementary File S1 Unpublished OCP data
Text of Coffeng et al. (2014a)
Uniform distribution [0,1] Habbema et al. (1996a)
100% Plaisier et al. (1995)
Weibull distribution with mean 1 and Plaisier et al. (1995)
293
shape 2
(Continued)
Table 3 Definition and values of variables and parameters for ONCHOSIMdcont'd

294
Parameter Values and Units Sources
Duration of embryostatic 11 months
effect (Tr, s)
Per dose (cumulative) reduction in 35%
worm fecundity, d
Macrofilaricidal efficacy 0%
Assumption set 2
Embryostatic effect (tau) Exponential distribution with mean 3.5 Coffeng et al. (2014a)
(years)
Macrofilaricidal efficacy (on male Beta distribution with mean 12.3% and
worms) sample size 50
Macrofilaricidal efficacy (on female Beta distribution with mean 6% and
worms) sample size 50
Larviciding
Timing User-defined Plaisier et al. (1997)
Coverage User-defined

M.G. Bas
an
~ez et al.
River Blindness 295

particular. The precursors of EPIONCHO (Bas
an ~ez and Boussinesq, 1999;

Bas
an~ez and Ric
ardez Esquinca, 2001; Bas
an
~ez et al., 2002, 2007), based on
(deterministic) differential equations, were developed with the primary
objective of understanding the impact of parasite population regulatory pro-
cesses on the population biology of O. volvulus and the transmission dy-
namics of onchocerciasis. These precursors were subsequently extended to
explore the influence of parasite overdispersion (Churcher et al., 2005,
2006), to include human host age- and sex-structure (Filipe et al., 2005),
to account for parasite population genetic structure with the aim to investi-
gate the spread of anthelmintic resistance (Churcher and Bas
an ~ez, 2008,
2009) and to add realism regarding treatment coverage and adherence pat-
terns (Turner et al., 2013a), thus evolving into a full-transmission and con-
trol model capable of supporting decision-making by intervention
programmes. ONCHOSIM is an individual-based model for simulating
onchocerciasis transmission and control in a dynamic human population,
based on the technique of stochastic microsimulation (Alley, 1992; Hab-
bema et al., 1996b). The underlying generalized modelling framework has
formed the basis of similar models for other helminthic diseases (De Vlas
et al., 1996; Plaisier et al., 1998). ONCHOSIM was conceived from the start
with the purpose of informing control strategies (Remme, 2004a), formerly
during the OCP (Habbema et al., 1996a; Plaisier et al., 1990,b, 1997;
Remme et al., 1986; Remme et al., 1990a), and more recently to support
APOC’s elimination efforts and to quantify its overall health impact (Cof-
feng et al., 2013a, 2014a).
A formal comparison of EPIONCHO and ONCHOSIM regarding
the required duration of mass ivermectin treatment for onchocerciasis
elimination in Africa has been presented by Stolk et al. (2015). In this pa-
per, the two models were ‘docked’ as much as possible in terms of param-
eter values (see Table 2 of Stolk et al., 2015), and the focus was on
comparing, contrasting and understanding the similarities and differences
in projected elimination outcomes (under annual or biannual ivermectin
distribution) for a number of epidemiological scenarios (defined in terms
of initial endemicity, microfilarial prevalence, CMFL and vector biting
rates), ranging from mesoendemic to holoendemic onchocerciasis, and a
number of programmatic scenarios (defined by therapeutic coverage and
treatment adherence). This comparison revealed several differences in
model predictions, despite harmonization of key parameters. The
remainder of this section discusses some of the convergences and diver-
gences identified.
296 ~ez et al.
M.G. Bas
an

EPIONCHO is a deterministic, population-based model; ONCHOSIM

is a stochastic individual-based model. Although there are some similarities,
the models also differ in important aspects, e.g., on the extent to which het-
erogeneities in the human population (e.g., in exposure to blackfly bites) and
density dependencies in various processes are captured (e.g., in parasite
establishment rate within humans and excess mortality of infected flies, as
described above). More specifically, and in the context of the ability of
both models to predict elimination, EPIONCHO does not account for
the possibility of chance elimination of the parasite population (stochastic
fadeout), which becomes increasingly likely at very low intensities of infec-
tion, especially for small settings (villages) with a couple of hundred inhab-
itants (as assumed by ONCHOSIM). Secondly, the models differ with
respect to assumptions about density dependence in the various processes
involved in transmission dynamics (Table 4), which may also be important
for elimination prospects (Duerr et al., 2005, 2011). In particular, EPION-
CHO includes a (negative) density-dependent relationship between the
annual transmission potential and the parasite establishment rate (Section
2.1.1.1); ONCHOSIM does not capture this mechanism, which makes
the model more optimistic regarding elimination prospects. Thirdly, the
assumed distribution of adult worm and microfilarial survival times and as-
sumptions regarding microfilarial productivity in relation to worm age
may play a role. The current version of EPIONCHO assumes an exponen-
tial distribution of worm survival times with a long right tail, implying that
worm mortality rates are independent of worm age (an implicit assumption
of the exponential model). ONCHOSIM assumes a Weibull distribution
(Plaisier et al., 1991a), a more symmetrical distribution with the same
mean survival time but a shorter right tail, implying age dependency of
worm mortality rates (Section 2.2.2.3). Therefore, it takes considerably
longer for the parasite population to die out naturally in EPIONCHO
than in ONCHOSIM. In addition to this, ONCHOSIM assumes that the
microfilarial production rate declines in older worms (Section 2.2.2.3), so
that the relatively old worm population remaining after long-term iver-
mectin mass treatment has a relatively low microfilarial production. Such
a process is not considered by EPIONCHO. EPIONCHO models micro-
filarial prevalence as a function of mean microfilarial density assuming an un-
derlying negative binomial distribution whose overdispersion parameter is a
function of the mean (such that the distribution becomes increasingly aggre-
gated as the intensity of infection decreases). In ONCHOSIM individual
outputs are aggregated to obtain information on the microfilarial prevalence
River Blindness 297

Table 4 Overview of the main characteristics of the EPIONCHO and ONCHOSIM

models
Characteristics EPIONCHO ONCHOSIM
Basic model structure
Modelling approach Deterministic, Stochastic, individual-
population mean- based (excepting the
based vector component)
Number and type of Single population Single population
spatial locations
modelled
Way of representing Mean density in Presence and density at
infection in hosts population subgroups individual level
(e.g., age, sex,
treatment adherence
group). Prevalence as
a function of mean
density assuming an
underlying negative
binomial distribution
Interventions Mass treatment Mass treatment,
considered in selective treatment
previous publications (test-and-treat),
vector control
Features included in the model
Human population Birth and death rate; age Birth and death rate; age
demographics and sex composition and sex composition
Heterogeneities in the Age, sex, life Age, sex, life
human population expectancy, level of expectancy, level of
exposure to blackflies, exposure to blackflies,
adherence with MDA adherence with
MDA, treatment
efficacy
Blackfly population Fixed input as annual Fixed input as annual
density biting rate (ABR); biting rate (ABR);
seasonality in biting seasonal monthly
rates can be included biting rates
Exposure to blackfly Heterogeneous Heterogeneous
vectors (dependent on age (dependent on age,
and sex) sex, personal
attractiveness to
blackflies)
(Continued)
298 ~ez et al.
M.G. Bas
an

Table 4 Overview of the main characteristics of the EPIONCHO and ONCHOSIM

modelsdcont'd
Characteristics EPIONCHO ONCHOSIM
Uptake of infection by Varying non-linearly
blackfly vectors (density-dependent)
with infection
intensity in human
hosts
Infection in blackfly Density (average L3 load
vectors per fly)
Excess mortality of Yes
infected flies
Parasite acquisition in Nonlinearly (density-
humans dependent) related to
rate of exposure to L3
larvae
Infection in humans Density (nonfertile and
fertile worms, mf per
mg of skin)
Diagnostic outcomes Sampling process and
diagnostic
performance of skin
snipping not yet
included
Elimination end-points pOTTIS and
transmission
breakpoints; does not
account for stochastic
fade-out
Adapted from Stolk, W.A., Walker, M., Coffeng, L.E., Bas
an ~ez, M.G., de Vlas, S.J., 2015. Required
duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative
modelling analysis. Parasit. Vectors 8, 552.
Varying non-linearly
(density-dependent)
with infection
intensity in human
hosts
Density (average L3 load
per fly)
No
Linearly proportional to
mean number of L3
larvae inoculated,
denoted by the
success ratio
Density (immature or
mature worms, mf per
skin snip)
Microfilarial count
sampling to relate
model predictions to
data
pOTTIS and probability
of elimination;
stochastic fade-out
possible

(proportion of individuals with a positive microfilarial count in either of two

skin snips) and intensity. Lastly, the distribution of adult worms among the
human population will play a role again through its influence on the mating
probability. This assumed distribution is explicit in EPIONCHO (Section
2.1.1.2) and implicit in ONCHOSIM, driven by between-host heterogene-
ities in exposure and adherence with treatment (Section 2.2.2.3) (Stolk et al.,
2015). Table 4 gives an overview of structural similarities and differences be-
tween the two models; Table 5 compares parametric assumptions by the two
models.
River Blindness 299

Table 5 Overview of current parametric assumptions by EPIONCHO and ONCHOSIM

Parametric assumption EPIONCHO ONCHOSIM

Human population size Large Small, maximum

population size of 440
people
Demography of the Following survivorship Reflecting survivorship
human host function for function for sub-
population Cameroon; good Saharan Africa
agreement with OCP
reference population
Blindness and excess Blindness and excess Blindness is a function of
mortality of the mortality are cumulative parasite
human host associated functions of load and blind
with onchocerciasis microfilarial load; the individuals have their
latter is a sigmoid remaining life
function, with a expectancy shortened
higher mortality risk, by 50% on average
for a given
microfilarial load, for
those aged 20 years or
less
Parameterized for Yes Yes
O. volvulusesavannah
species of Simulium
damnosum s.l.
Parameterized for No No
O. volvuluseforest
and forestesavannah
mosaic species of
Simulium damnosum
s.l.
Proportion of blood h, varied between 0.1 1  z ¼ 0.96 (where z
meals taken by and 0.99; set at 0.3 for is the zoophagy
vectors on humans Cameroon; set to index, set at 0.04)
0.96 for formal model
comparison
Life expectancy of adult 10 years 10 years
worms
Distribution of adult Exponential Weibull
worm survival times
Parasite establishment dH, a (negative) density- sr, a density-
probability within dependent function independent constant
human hosts of the number of L3 set at 0.0031
larvae received per
year (following a
(Continued)
300 ~ez et al.
M.G. Bas
an

Table 5 Overview of current parametric assumptions by EPIONCHO and

ONCHOSIMdcont'd
Parametric assumption EPIONCHO ONCHOSIM
non-linear
relationship between
microfilarial load and
annual transmission
potential) (Eq. (2)),
varying between a
maximum value of
0.0854 and a
minimum of 0.00299
Contribution to skin 2.4 to 5.8 microfilariae/ cw ¼ 7.6 microfilariae/
microfilariae per worm worm
female worm
Life expectancy of 15 months, assuming Fixed at 9 months,
microfilariae exponential assuming that all
distribution of microfilariae live for
survival times 9 months and then
die
Skin microfilarial load M, the mean number of sl, the number of
microfilariae per mg microfilariae per skin
of skin; EPIONCHO snip (ss);
has used a snip weight ONCHOSIM
of 1.7e2.84 mg assumes a weight of
2 mg per snip
Prophylactic efficacy Not included Not included
Microfilaricidal efficacy 98%e99%, 2 mo. after 100%, instantaneous
treatment reduction
Embryostatic effect Fertile worms exposed All female worms
to ivermectin temporarily stop
decrease their producing
microfilarial microfilariae but
production according resume production
to the dynamics gradually, reaching
~ez
presented in Bas
an maximum production
et al. (2008) and capacity 11 months
would fully recover if post-treatment on
further untreated average (Plaisier et al.,
1995)
Macrofilaricidal efficacy 0% 0% or 12.3% for male
worms and 6% for
female worms; set to
0% for formal model
comparison
River Blindness 301

Table 5 Overview of current parametric assumptions by EPIONCHO and

ONCHOSIMdcont'd
Parametric assumption EPIONCHO ONCHOSIM
Cumulative, per dose 0%, 7%, 30%, set to 35% 35%
reduction in female for formal model
worm fertility comparison
Parasite establishment dV, a (negative) density- A (negative) density-
probability within dependent function dependent function
vector hosts of microfilarial load of microfilarial load
per mg (following a per ss (following an
hyperbolic exponential
relationship between relationship between
L1 uptake and L1 uptake and
microfilarial load, Eq. microfilarial load, Eq.
(6)), varying between (54)), varying
a maximum of 0.0207 between 0.0511 and
and zero zero. (Note that
converting ss into mg,
the maximum
probability would be
0.0256)
Maximum number of 1.4 1.2
L1 larvae establishing
within the fly as
microfilarial load
becomes infinitely
large
Mortality rate of vectors Increases linearly with Density independent
microfilarial load,
Eq. (8)
Background probability 0.87 0.78
of daily survival by
vectors
Probability that an 0.54e0.8 0.65
infective, L3 larva is
shed, per bite
Survival probability of 0.75 0.90
L3 larvae (if not shed)

As a consequence of the above, and for the comparison presented in

Stolk et al. (2015), EPIONCHO predicted (under either annual or biannual
mass ivermectin distribution) a faster initial decline in both microfilarial
prevalence and intensity for all the epidemiological scenarios explored,
302 ~ez et al.
M.G. Bas
an

but the decline levelled off and the two infection indicators tended to move
towards a new equilibrium, possibly as a consequence of (negative) density
dependence. In ONCHOSIM, the initial decline in infection levels was less
pronounced and so was the levelling-off in the long term. Eventually, the
infection indicators reached zero faster in ONCHOSIM than in EPION-
CHO. The difference between the two models was more pronounced for
the microfilarial prevalence than for the mean microfilarial intensity,
prompting modifications to the way that EPIONCHO models prevalence
(Walker et al., unpublished data).

3. MODEL VALIDATION
3.1 EPIONCHO
EPIONCHO outputs have been compared against published (Bas
an ~ez
and Boussinesq, 1999) precontrol data on microfilarial prevalence (the gold
standard measure of infection prevalence) and annual vector biting rates
from Burkina Faso, Cameroon and C^ ote d’Ivoire (Fig. 5). EPIONCHO
matched the pattern in the data very closely by modifying the human blood
index (h, the proportion of blood meals taken on humans) of the blackfly
vectors. This modification was motivated by recent (molecular-based) esti-
mates obtained from field samples collected in Ghana (Lamberton et al.,
2012, 2016). The proportion of blood meals taken on humans was increased

Figure 5 Validation of EPIONCHO against precontrol microfilarial prevalence data from

Burkina Faso, Cameroon and Co ^te d’Ivoire (Bas
an
~ez and Boussinesq, 1999). The solid line
represents the predicted endemic equilibrium prevalence of skin microfilariae in the
human population for different values of the annual biting rate (the number of vector
bites per person per year) assuming a human blood index of 67% for the savannah
members of the Simulium damnosum s.l. complex.
River Blindness 303

Figure 6 Validation of EPIONCHO and ONCHOSIM against longitudinal microfilarial

prevalence data from foci where onchocerciasis has been eliminated with mass distri-
bution of ivermectin. The solid and dashed lines are projections from EPIONCHO and
ONCHOSIM, respectively. Data points are from mesoendemic (left panel) and hyperen-
demic (right panel) endemic communities in the river Gambia, Senegal (Diawara et al.,
2009). Treatment was yearly in 1988 and 1989, and 6-monthly from 1990 onwards.
Models are fitted to the precontrol microfilarial prevalence by modifying the annual
biting rate of blackfly vectors. The cumulative antifecundity effect of ivermectin was
set to 35% per dose for both models (Plaisier et al., 1995).

from one-third to two-thirds (for the savannah members of the S. damnosum

species complex).
In addition, EPIONCHO has been validated (and compared with
corresponding ONCHOSIM projections) against longitudinal data on
microfilarial loads (the gold standard measure of infection intensity) from
sentinel communities in Mali and Senegal where annual and biannual
treatments with ivermectin were sufficient to eliminate the infection in
approximately 15 years (see Fig. 6 for Senegal). EPIONCHO captured
well the long-term longitudinal trends in the data and matched closely
the projections of ONCHOSIM when a similar assumption was imple-
mented on the severity of the cumulative effect of ivermectin on the fertility
of adult female O. volvulus. Formerly, a 7% cumulative reduction on adult
female worm fertility had been used as nominal value and varied in sensi-
tivity analysis (Turner et al., 2014a,c). By increasing this magnitude to
35%, results are closer to those of ONCHOSIM, indicating that this is a
crucial assumption in the models, which needs to be scrutinized further
(Stolk et al., 2015).

3.2 ONCHOSIM
ONCHOSIM was first published in 1990 (Plaisier et al., 1990) and since
then model predictions have frequently been compared with observed
data for model fitting and validation. The model has been shown to mimic
adequately trends in infection prevalence, infection intensity and
304 ~ez et al.
M.G. Bas
an

microfilarial count frequency distribution during vector control (Plaisier

et al., 1991a,b), changes in infection intensity for a cohort of people
following a single treatment or repeated annual treatments with ivermectin
(Plaisier et al., 1995) and average trends in microfilarial prevalence during
long-term ivermectin mass treatment (Coffeng et al., 2014a; Tekle et al.,
2016). The model also adequately captures the precontrol association
between community-level microfilarial prevalence and prevalence of blind-
ness as well as trends in blindness prevalence during vector control (Coffeng
et al., 2013a).
A more formal validation of EPIONCHO and ONCHOSIM regarding
their ability to model microfilarial prevalence temporal trends and subse-
quent elimination in the Mali and Senegal foci where this has been success-
fully achieved (Traore et al., 2012) is underway and will be presented
elsewhere (Walker et al., unpublished data).

4. MODELLING CURRENT TREATMENT STRATEGIES

In this section we turn our attention to the modelling of current, mass
treatment, strategies based on annual (and biannual) ivermectin distribution.
Biannual ivermectin treatment has been included among the alternative
intervention strategies, particularly for those foci and projects that are not
progressing well under the annual strategy e but are not coendemic with
loiasis e or have not yet started/are starting large-scale implementation.
However, we include biannual treatment in this section because some
countries (e.g., Ghana, Ethiopia) have already switched to 6-monthly iver-
mectin distribution (Carter Center, 2013; Turner et al., 2013b; Frempong
et al., 2016), or have been successful in achieving elimination in some foci
by doing so (e.g., Sudan, Uganda) (Higazi et al., 2013; Katabarwa et al.,
2012; Katabarwa and Richards, 2014). The same rationale applies to the
increasing of therapeutic coverage and reduction of nonadherence to
treatment, the impact of which is also discussed in this section. Therefore,
this section presents our attempts to tackle the first question posed by the
NTD Modelling Consortium, namely, ‘under which epidemiological
scenarios do models predict that onchocerciasis can be eliminated with
current strategies?’ We restrict ourselves to discussing epidemiological sce-
narios where species of the S. damnosum s.l. are the main vectors (i.e., we
do not consider S. neavei-transmitted onchocerciasis as in those, East African,
foci where this species prevails, onchocerciasis elimination has been aided by
River Blindness 305

elimination of the vector (Garms et al., 2009; Lakwo et al., 2013), which is
facilitated by its very particular breeding site ecology in phoretic association
with freshwater Potamonautes crabs).
We commence by defining elimination endpoints, i.e., what are the
targets to be achieved and how do the models quantify time to elimination
and programme duration.

4.1 Defining elimination endpoints

Most recent applications of EPIONCHO and ONCHOSIM e
particularly since the switch from onchocerciasis morbidity control to
elimination e have focused on exploring the feasibility of MDA-based
interventions in achieving elimination endpoints within the time horizons
defined by the WHO’s 2020 and 2025 elimination targets described in
Section 1.2.4 above (Turner et al., 2014c; Coffeng et al., 2014a). The (pos-
itive) density-dependent transmission processes built into EPIONCHO
(e.g., the mating probability) ensure a theoretical ‘breakpoint’ parasite den-
sity below which transmission would be unsustainable and the parasite
population would decline terminally until (local) elimination (Anderson
and May, 1985). Such breakpoints are multidimensional, depending on
the density of each parasite stage, but particularly the longest-lived adult
stage (Duerr et al., 2011). Under equilibrium conditions, or by applying
simplifying assumptions on the dynamical responses elicited by interven-
tions, breakpoints can be explored analytically (Bas
an~ez et al., 2009; Duerr
et al., 2011). More generally, they must be assessed from numerical
outputs, evaluating the parasite population projections after cessation of a
simulated intervention. Many of the population processes that ensure a
deterministic breakpoint in EPIONCHO also apply when elimination is
achieved in ONCHOSIM, albeit with the crucial difference that the
stochastic nature of ONCHOSIM permits elimination by chance, so-
called ‘stochastic fade-out’. The importance of stochastic fade-out
compared to the influence of breakpoints inherent to the transmission
process will be presented elsewhere but has been briefly discussed by Stolk
et al. (2015).
The somewhat hypothetical and elusive nature of parasite breakpoints
has motivated the use by EPIONCHO of the more pragmatic and
programmatically relevant provisional operational (prevalence) thresholds
for treatment interruption and commencement of surveillance that were
proposed by APOC (2010) in its conceptual and operational framework
for onchocerciasis elimination with ivermectin treatment. These
306 ~ez et al.
M.G. Bas
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thresholds, referred to as pOTTIS are (1) a microfilarial prevalence (by skin

snipping) of <5% in all surveyed villages and <1% in 90% of such villages,
and (2) fewer than 0.5 infective larvae per 1000 dissected flies (0.05% flies
with L3 larvae). It has been assumed that when the modelled microfilarial
prevalence (all ages) falls to <1.4% (the weighted mean of the two preva-
lence thresholds above), measured just before the next treatment round,
the pOTTIS has been achieved, in turn, determining MDA programme
duration and number of treatment rounds required (Turner et al., 2014c,
2015b; Stolk et al., 2015). The focus on microfilarial prevalence is because
the entomological threshold is reached sooner than the microfilarial
prevalence threshold, and therefore the former is deemed to be the more
conservative indicator. It is important to reiterate that pOTTIS does not
truly represent a transmission breakpoint, but rather a programmatic goal
that indicates cessation of MDA and inception of post-MDA surveillance.
As pOTTIS values are provisional (APOC, 2010), they have always been
varied in sensitivity analyses. We refer the reader to Table 2 of the recent
formal comparison presented by Stolk et al. (2015), in which some param-
eter assumptions were harmonized between the two models to facilitate
evaluation of similarities and differences in model outputs. Tables 3 and
4 of Stolk et al. (2015) summarize, respectively, intervention scenarios
and precontrol epidemiological values used by EPIONCHO and
ONCHOSIM for model comparison.
In ONCHOSIM, the probability of elimination has typically been
assessed as the proportion of simulations in 1000 runs that result in elimina-
tion, where elimination is defined as absence of infection in the human pop-
ulation (as diagnosed by skin snipping) 50 years after the last mass treatment.
Simulation results are then used to determine minimum programme duration
and number of treatment rounds required to achieve 99% probability of
elimination (Coffeng et al., 2014a). Work is underway to explore how this
probability of elimination e under different transmission settings e relates
to the current pOTTIS, with the aim of refining this still provisional and
operational ‘elimination’ threshold for use as a comparator with the results
of field epidemiological evaluations.

4.2 Treatment with ivermectin

Both EPIONCHO and ONCHOSIM have been used extensively to eval-
uate the long-term impact of ivermectin MDA on infection levels and on
the attainment of elimination goals. Modelling evaluations have been con-
ducted under a variety of scenarios that broadly cover the range of
River Blindness 307

epidemiological and programmatic settings that occur in the APOC and

former OCP transmission zones. Particular attention has been paid to the
triplicate questions: ‘how long to treat, at what frequency and at what
coverage?’ However, it is noteworthy that both models have yet to explicitly
capture the different epidemiology and ecology of forest and savannah
onchocerciasis, particularly with respect to the differential competences of
the wide variety of blackfly species and subspecies found across the African
~ez et al., 2009).
continent (Adler et al., 2010; Bas
an

4.2.1 Epidemiological and programmatic variables

4.2.1.1 Initial level of onchocerciasis endemicity
A modelling study based on ONCHOSIM (Winnen et al., 2002) had
concluded that precontrol endemicity was highly influential on the duration
of treatment required to eliminate infection. Higher endemicity levels were
associated with longer programme durations, findings later corroborated by
refined simulations using both EPIONCHO and ONCHOSIM (Turner
et al., 2014c; Coffeng et al., 2014a). EPIONCHO has been used to explore
the impact of three values of initial prevalence of microfilaridermia, namely,
40% (mesoendemic), hyperendemic (60%) and highly hyperendemic or hol-
oendemic (80%) (Turner et al., 2014c). ONCHOSIM projections have used
precontrol CMFL values of 5 and 10 microfilariae per skin snip as represen-
tative of APOC areas that were mesoendemic before the start of control, and
of 30, 55 and 80 mf/ss as representative of hyperendemic areas (with 80 mf/
ss corresponding to highly hyperendemic areas) (Coffeng et al., 2014a).

4.2.1.2 Treatment frequency

EPIONCHO has been used to investigate the long-term impact on
parasitological variables (skin microfilarial prevalence and intensity) of annual
ivermectin treatment (the strategy mainly used thus far by APOC) vs. switching
to biannual (6-monthly) treatment or implementing biannual treatment from
the start of the programme (strategies adopted in some African foci) (Turner
et al., 2013a, b). ONCHOSIM has explored the impact of annual (continuing
the current strategy) vs. switching to biannual or 3-monthly (quarterly) iver-
mectin treatments (Coffeng et al., 2014a). Projections using both models have
indicated a 30e40% reduction in the remaining time required to reach elim-
ination endpoints by switching to the biannual treatment strategy, albeit
contingent on maintaining high levels of coverage (Coffeng et al., 2014a)
and a low proportion of people who never adhere to treatment, the so-called
systematic noncompliers (Turner et al., 2014c).
308 ~ez et al.
M.G. Bas
an

4.2.1.3 Treatment coverage and adherence

In both EPIONCHO and ONCHOSIM, coverage is typically expressed as
the proportion of the total population who receive treatment at a particular
treatment round. Typically, about 15% of the total population is noneligible
for ivermectin treatment for age, weight, pregnancy or illness reasons. For
example, 80% of the total population corresponds to a coverage of about
95% of eligibles and 60% of the total population corresponds to a coverage
of 85% of eligibles. This definition of coverage is in line with APOC’s but
other programmes, notably OEPA, use coverage of eligibles rather than of
total population. The effect of three levels of therapeutic coverage
throughout the treatment programme has been investigated with EPION-
CHO, namely 40% (poor), 60% (moderate) and 80% (high) coverage of the
total population (Turner et al., 2014c), in addition to varying (independently
of coverage) the level of systematic nonadherence between 0.1% and 5%.
ONCHOSIM has explored the impact of historical coverage levels of
50% (low), 65% (intermediate) and 80% (high) and varied these to be
15% higher or lower subsequently; the proportion of the population who
never takes treatment is set at 5% (Coffeng et al., 2014a). Projections using
both models (Figs. 7 and 8) have highlighted the importance of maintaining
high levels of therapeutic coverage and avoiding high proportions of system-
atically noncompliant individuals in reaching elimination time points within
reasonable time horizons.
According to these studies, and in answer to the first question posed by
the NTD Modelling Consortium, EPIONCHO and ONCHOSIM both
predict that in mesoendemic areas (microfilarial prevalence of 50% and
CMFL of 6 mf/ss) e provided that moderate to high levels of therapeutic
coverage can be achieved and maintained the pOTTIS can be reached
with annual treatment in 12e18 years. In hyperendemic areas (microfilarial
prevalence greater than 60% but lower than 80% and CMFL of 10 mf/ss),
the pOTTIS could be reached with 14e17 years of annual treatment only
if therapeutic coverage is at least 80%. In highly hyperendemic areas (micro-
filarial prevalence greater than 80% and CMFL of 30e80 mf/ss) this strategy
is insufficient or would require prolonged continuation of treatment
(incompatible with the proposed time horizons). For the lower endemicity
levels explored, ONCHOSIM predicted that the time needed to reach the
pOTTIS is longer than that required to drive the parasite population to
elimination, whereas for the higher endemicity levels the pOTTIS was
reached earlier than parasite elimination. In EPIONCHO, the pOTTIS
was reached consistently sooner than the transmission breakpoint. This
River Blindness 309

Figure 7 Comparison of the impact of annual and biannual ivermectin treatment on

onchocercal microfilarial intensity according to EPIONCHO. Annual and biannual iver-
mectin treatments are indicated by solid and dashed lines, respectively. The light
grey, dark grey and black lines correspond, respectively, to a precontrol endemicity
of 40% (mesoendemic, A), 60% (hyperendemic, B), and 80% (highly hyperendemic,
C) microfilarial prevalence. Microfilarial intensity is quantified as the mean microfilarial
load (mf) per milligram of skin in those aged 20 years. The analysis was performed
assuming a therapeutic coverage of 80%, 0.1% systematic noncompliers, perennial
transmission and a 7% cumulative reduction in microfilarial production by female adult
worms per ivermectin dose (Turner et al., 2014c).

suggests that the operational thresholds proposed by APOC may have to be

adjusted to reflect more adequately the impact of precontrol endemicity,
i.e., a one-size-fits-all pOTTIS may not be appropriate in all epidemiolog-
ical settings and should be revised in light of further modelling work to bet-
ter guide elimination efforts in Africa (Stolk et al., 2015).

5. MODELLING ALTERNATIVE INTERVENTION

STRATEGIES
In this section we summarize work conducted towards tackling the
second question posed by the NTD Modelling Consortium: in those sce-
narios where elimination cannot be achieved using the current strategy,
which (and where) alternative and complementary intervention strategies
should be deployed to facilitate/accelerate progress towards elimination.
In settings with particularly intense transmission, typically driven by high
blackfly biting rates, simulations from ONCHOSIM and EPIONCHO
have indicated that elimination may not be feasible in reasonable timeframes,
310 ~ez et al.
M.G. Bas
an

Figure 8 Predicted minimum remaining programme duration required until elimina-

tion of onchocerciasis according to ONCHOSIM. The assumptions regarding ivermectin
effects are as in assumption set 1 of Table 3. Panels illustrate the minimum remaining
programme duration (y-axis) required for 99% probability of elimination (absence of
infection 50 years after the last mass treatment), given the number of annual mass
treatment rounds already completed (x-axis) (1000 simulations per scenario). Each
 River Blindness 311

even under biannual ivermectin MDA with high levels of therapeutic

coverage and low systematic noncompliance (Coffeng et al., 2014a; Stolk
et al., 2015). Moreover, ivermectin MDA is contraindicated in foci where
loiasis is coendemic with low to moderate levels of onchocerciasis due to
the unacceptable risk-benefit ratio of potential SAEs following treatment.
In coendemic settings with higher onchocerciasis endemicity, ivermectin
is indicated, but not under the usual community-directed approach; clini-
cally trained staff are required to follow-up individuals after treatment to
monitor for signs of SAEs (Mectizan Expert Committee and Technical
Consultative Committee, 2004). These more complex protocols, together
with a perception of risk provide an impediment to ivermectin MDA in
loiasis-onchocerciasis coendemic areas or nearby areas, with the
consequence of programmes attaining low levels of coverage and treatment
adherence (Wanji et al., 2015a,b). Therefore, many communities, particu-
larly in forested regions of west-central Africa, are de facto inadequately
served by current strategies for onchocerciasis control.
Consequently, alternative intervention strategies (see Section 1.3 above
for general background to some of these) are being considered for both
high endemicity settings, to intensify or complement ongoing ivermectin
MDA, and loiasis-onchocerciasis coendemic settings to provide alternatives
to ivermectin MDA. Alternative strategies are also envisaged as a potential
means to accelerate progress towards elimination in a variety of
epidemiological and programmatic contexts, including areas where

=---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
panel compares four strategies: continuing annual mass treatment at same coverage
(solid black line), switching to 6-monthly mass treatment at same coverage (dashed
black line), switching to 3-monthly mass treatment at same coverage (dotted black
line), or continuing annual treatment at increased (þ15% points) coverage (solid grey
line; only for past coverage of 50% and 65%). Different panels pertain to increasing
pre-control infection levels (top to bottom), and increasing values of past mass
treatment coverage (left to right). Grey lines represent smoothed (and where relevant)
extrapolated trendlines of simulated outcomes, fitted such that they intersect with the
x-axis at the same point as graph lines for annual mass treatment (black solid lines).
Values in the corner of each panel represent reductions in remaining programme dura-
tion (pooled over scenarios for different numbers of past treatment rounds), when
increasing coverage (a), switching to 6-monthly mass treatment (b), or switching to
3-monthly mass treatment (c), compared to continuing annual treatment at the
same coverage. Panels marked with an asterisk (*) pertain to simulations that did not
result in 99% probability of elimination within 20 future treatment rounds, and hence
contain no graph lines (Coffeng et al., 2014a).
312 ~ez et al.
M.G. Bas
an

suboptimal responses to ivermectin have been reported (Osei-Atweneboana

et al., 2007; Frempong et al., 2016); to ‘mop-up’ where transmission has
been interrupted but where infection persists, and to protect against recru-
descence in communities freed from infection.

5.1 Moxidectin treatment

EPIONCHO has been used to explore the impact of MDA with moxidec-
tin on the feasibility of reaching elimination (pOTTIS) endpoints by varying
the same epidemiological and programmatic variables explored under iver-
mectin-based intervention strategies (Section 4.2). A principal and intuitive
conclusion arising from the superior efficacy of a single-dose of moxidectin
compared with ivermectin is that an annual moxidectin MDA intervention
is about as effective as a biannual ivermectin strategy. Somewhat more subtle
is that the impact of moxidectin is much less susceptible to the timings when
treatment rounds are administered with respect to seasonal peaks in transmis-
sion because of the more prolonged suppression of microfilaridermia
affected by moxidectin compared with ivermectin. This was demonstrated
by modelling two seasonal transmission scenarios: (1) an extreme scenario
with transmission occurring during a rainy season typically lasting between
four and five months each year, based on the entomological situation in foci
of Senegal, Mali (Diawara et al., 2009; Traore et al., 2012) and Nigeria
(Tekle et al., 2012), where elimination has been reported, and (2) a longer
period of transmission, still peaking in the rainy season but not ceasing
completely in the dry season, motivated by the entomological observations
conducted in Nigeria and reported by Opara et al. (2005). In both scenarios,
and in the absence of vector control operations, the entomological condi-
tions during the treatment programme remain unchanged, or vector den-
sities would have recuperated to original values if there had been vector
control during the OCP years (Lamberton et al., 2014).

5.2 Macrofilaricidal treatment

The impact of a hypothetical macrofilaricidal drug as a complement to
microfilaricidal ivermectin MDA and vector control, or as an alternative
intervention in communities not served by onchocerciasis control, has
been considered using ONCHOSIM under the assumption that the drug
would kill or (permanently) sterilize 95% of all adult worms (Alley et al.,
2001). Duerr et al. (2011) used their mathematical model (Duerr et al.,
2003, 2004) to examine the question of transmission breakpoints with re-
gard to vector biting rates and the required effectiveness of CDTI necessary
River Blindness 313

to drive the parasite population to elimination. These authors concluded

that a macrofilaricidal effect would support control efforts by lowering
this minimum required effectiveness, but that the advantages conferred by
a macrofilaricidal effect would be inversely related to the magnitude of
the vector biting rate. For annual biting rates exceeding 10,000 bites per
person per year, the beneficial impact of a macrofilaricidal effect was
predicted to diminish substantially. The predictions from the Duerr et al.
(2011) model were more pessimistic than those of Alley et al. (2001) using
ONCHOSIM, and this was deemed to be due to the larger number of
density-dependent processes in the former compared to the latter, an issue
that also pertains to EPIONCHO. Presently, neither EPIONCHO nor
ONCHOSIM assumes a macrofilaricidal effect of ivermectin.
However, and more recently, a novel component of EPIONCHO has
been developed to capture the activity of anti-wolbachial, macrofilaricidal,
therapies on the population dynamics of O. volvulus (Walker et al., 2015).
This submodel considers the dynamics of the mean number of Wolbachia-
positive, Wolbachia-depleted and Wolbachia-negative adult worms per host.
The model has been fitted to immunohistological data on adult worms
collected at various times after a 4-, 5- or 6-week course of 100 mg or
200 mg of doxycycline per day, during clinical trials (Hoerauf et al., 2003,
2008, 2009). By explicitly considering the rate of Wolbachia depletion and
the excess mortality rate incurred by Wolbachia-depleted and Wolbachia-
negative adults, this analysis showed that, irrespective of the particular
drug regimen, doxycycline is a highly efficacious macrofilaricide, depleting
Wolbachia from >95% of worms in a majority of hosts and reducing the life-
span of O. volvulus by 70e80%, from about 10 (Plaisier et al., 1991a) to 2e
3 years. By incorporating this parameterized anti-wolbachial macrofilaricidal
component into EPIONCHO, preliminary simulations have indicated that
a single dose of doxycycline, given en masse, is about twice as effective in
reducing microfilaridermia compared to ivermectin (Walker et al., 2012a).
This is because, albeit initially protracted, reductions in microfilaridermia
are sustained long into the future, and long after post-ivermectin microfi-
~ez et al., 2008), due to the (permanent) ster-
larial skin repopulation (Bas
an
ilization and macrofilaricidal action of doxycycline. Individual host-based
variants of EPIONCHO are being developed to complement planned
ONCHOSIM simulations of proposed test-and-treat strategies as these
will likely be the predominant way in which the current, relatively long,
courses of anti-wolbachial therapies will be delivered to target populations,
particularly those where loiasis is coendemic with onchocerciasis.
314 ~ez et al.
M.G. Bas
an

5.3 Vector control

In the context of contemporary control programmes, large-scale, pro-
longed and high-cost vector control initiatives such as those conducted
during the OCP years are unlikely to be implemented, however successful
(Hougard et al., 2001). Therefore, modelling should focus on quantifying
the impact on blackfly populations of alternative and more practicable low-
cost, ground-based larviciding techniques (Taylor et al., 2009), whose fre-
quency and duration need to be estimated according to the desired aim
(e.g., local elimination of the vector population; reduction of biting rates
below a specified threshold; reduction of biting rates in relation to treat-
ment timing, etc.).
Observations of biting densities of S. damnosum s.l. at breeding sites dur-
ing and after an interruption of insecticidal treatments suggest that assuming
instantaneous reductions and resumptions in the level of blackfly biting, as it
has been modelled previously (Plaisier et al., 1997), may be oversimplistic
and that, rather, the recolonization of such sites follows a temporal dynamics
governed by the population dynamics of the immature and adult blackfly
stages (Davies et al., 1981). To capture these, we have developed a blackfly
population dynamics model for S. damnosum s.l. based on ordinary differen-
tial equations that describe the rate of change with respect to time (and
temperature) of blackfly eggs, larvae, pupae, nulliparous imagoes and subse-
quent parous flies (which have obtained blood meals and oviposited), and
we have linked this model to the simplest (non host-age structured) version
of EPIONCHO (Cheke et al., 2015). Currently, the blackfly population
dynamics model is being fitted to OCP data concerning the dynamics or
recolonization of breeding sites after stopping weekly larviciding and subse-
quent reinception of insecticidal applications (Birley et al., 1983; Davies
et al., 1981). Once reparameterized to fit both the increase and decline in
daily biting rates observed, the vector model will be linked to the full version
of EPIONCHO described in Section 1.2 of this chapter to investigate the
impact on infection levels and attain elimination endpoints of localized
vector control when applied together with ivermectin MDA and other
alternative intervention strategies.
Other modelling studies (Duerr et al., 2011) have indicated that the shift
towards higher values of the threshold biting rate (the minimum vector
biting rate necessary of endemic persistence (Bas
an ~ez and Boussinesq,
1999; Dietz, 1982; Duer and Eichner, 2010) caused by CDTI may make
vector control measures more likely to succeed compared with vector
River Blindness 315

control or CDTI on their own. Partial and even minor vector control may
lead to elimination when CDTI alone has not driven parasite populations to
terminal decline.

5.4 An onchocerciasis vaccine

Although this intervention is at present more speculative than the ones
described above, the Onchocerciasis Vaccine for Africa (TOVA) Initiative
has been established and developed three candidate antigens that have
proven efficacious in three different filariae-animal systems (Hotez et al.,
2015). Based on target product profiles of both a preventive and a therapeu-
tic vaccine e targeting, respectively, the establishment of adult worms and/
or the microfilariae e EPIONCHO has been adapted to quantify the long-
term impact of a potential onchocerciasis vaccine by structuring the model
to capture the parasite population dynamics in vaccinated and nonvaccinated
human hosts. Vaccine efficacy was modelled using a set of partial differential
equations so that it wanes from an initial efficacy with respect to time and
host age at a specified rate (Turner et al., 2015a). By modelling a hypothet-
ical vaccination campaign aimed at 1- to 5-year-olds in its first year, repre-
senting an initial ‘catch-up’ campaign, followed by continuous vaccination
of 1-year-olds subsequently, Turner and co-workers concluded that an
onchocerciasis vaccine (1) could have a beneficial impact in onchocerci-
asiseloiasis coendemic areas, markedly reducing microfilarial load (and
ensuing disease burden) in people under 20 years of age; (2) could substan-
tially reduce the risk of recrudescence of onchocerciasis in areas freed from
infection after years of successful intervention, but (3) must critically have an
efficacy that wanes sufficiently slowly to protect adults, who tend to be more
exposed to blackfly bites than young children (Filipe et al., 2005). The
results of the modelling clearly showed the importance of obtaining reliable
estimates of the duration of vaccine protection (modelled as the reciprocal of
the rate at which vaccine efficacy would decay). This property of the vaccine
will be more important than initial vaccine efficacy in terms of the long-term
impact of any vaccination campaigns.

6. ECONOMIC EVALUATIONS
EPIONCHO (Turner et al., 2014c) and ONCHOSIM (Coffeng et al.,
2013a) have been used to conduct (model-based) economic evaluations of
MDA with ivermectin, and also, using EPIONCHO, of MDA with
316 ~ez et al.
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moxidectin (Turner et al., 2015b). In essence, both transmission models have

underpinned these economic evaluations in a similar manner, either in a sce-
nario-based framework (Turner et al., 2014c, 2015b), or using macroepide-
miological and programmatic data on infection prevalence and trends in
treatment coverage (Coffeng et al., 2013a). Model projections on infection
are coupled to projections on onchocerciasis-associated morbidity and mor-
tality, which in turn are converted to health metrics such as DALYs using
the latest and continually revised disease disability weightings (Coffeng
et al., 2014b). Combined with data on intervention cost (e.g., Turner
et al., 2013b), these metrics can be used to quantify cost effectiveness and
can be compared with other interventions and perhaps even against other
parasitic diseases, to inform decision-making on allocation of scarce resources.
Although the use of dynamic transmission models to conduct economic eval-
uations is relatively new in NTD research (Turner et al., 2014b; Lee et al.,
2015), the use of contemporary economic approaches for the evaluation of
onchocerciasis interventions was pioneered by Prost and Prescott (1984),
who used empirical effectiveness data to compare the cost effectiveness of vec-
tor control for blindness prevention in the OCP with that of a measles immu-
nization programme (Prescott et al., 1984).
In the next section we describe how the relationship between infection and
disease has been modelled in EPIONCHO and ONCHOSIM for the pur-
poses of quantifying effectiveness and ultimately cost-effectiveness analyses.

6.1 Burden of disease

Three principal onchocerciasis-associated sequelae have been thus far
coupled to outputs on the prevalence and intensity of O. volvulus infection
from EPIONCHO and ONCHOSIM to generate disease models with
which to quantify burden of disease, namely, (1) visual impairment,
including irreversible blindness, (2) severe itch (skin disease) and (3) excess
human mortality. This is not an exhaustive list and further refinements to
the disease models are required to better capture the relationship between
infection and other types of skin pathology (Ozoh et al., 2011) as well as
with neurological disorders such as epilepsy and nodding syndrome
(Colebunders et al., 2016a,b).

6.1.1 Blindness and visual impairment

In EPIONCHO, the number of blind people due to onchocerciasis, defined
as corrected visual acuity of <3/60 or restriction of visual field to less than
10 in the better eye (Remme, 2004b), has been modelled by the competing
River Blindness 317

rates of the incidence of new onchocerciasis-related blindness cases, and the

loss of already blind people due to excess mortality (Turner et al., 2014a).
The former was linked to microfilaridermia using a relationship estimated
from an analysis of the longitudinal OCP dataset collected from 1974
through 2001, which describes the incidence of blindness as a function of
the mean number of microfilariae per host lagged by two years, reflecting
that the loss of visual acuity is associated with past rather than present infec-
tion (Little et al., 2004a). The number of people with visual impairment or
low vision was assumed to be proportional to the number of prevalent cases
of blindness (Remme, 2004b). The method of modelling blindness in
ONCHOSIM is described in Section 2.2.2.5).

6.1.2 Skin disease

Both EPIONCHO and ONCHOSIM have based a relationship between
infection and skin disease on data demonstrating an association between
the prevalence of troublesome itch and the prevalence of palpable
onchocercal nodules in adult males (Murdoch et al., 2002). Since nodule
prevalence is not an output from either model, the use of this relationship
requires a further conversion between the prevalence of microfilariae and
nodule prevalence (Coffeng et al., 2013b) to provide a useable link between
infection and disease. Additionally, and parameterized using data from a
multicentre trial on ivermectin for treating onchocerciasis-associated skin
disease and severe itching (Brieger et al., 1998), EPIONCHO output has
been coupled to an initial rapidly acting ‘therapeutic’ effect of ivermectin
that manifests as an initial sharp decline in the prevalence of troublesome
itch followed by a more gradual decrease as the prevalence of adult worms
declines (Turner et al., 2014a).

6.1.3 Excess mortality

In ONCHOSIM, excess human mortality is considered in those individuals
who have already gone blind from onchocerciasis. That is, excess mortality is
associated with blindness rather than onchocerciasis per se (see Section
2.2.2.5). Similarly, EPIONCHO has been parameterized to include a rela-
tive risk of mortality of 2.5 and 1.5 in, respectively, blind and visually
impaired people compared to fully sighted individuals (Turner et al.,
2014a; Shibuya et al., 2006). However, in contrast to ONCHOSIM,
EPIONCHO has also included an excess mortality associated with heavy
infection, over and above that caused by blindness and visual impairment
(Section 2.1.1.3).
318 ~ez et al.
M.G. Bas
an

6.2 Costing intervention strategies

Costs have been incorporated into model-based economic evaluations of
onchocerciasis interventions in a variety of ways, and pertaining to different
programmatic economic and geopolitical levels. Turner et al. (2013b)
collected data on the cost of annual and biannual CDTI in Ghana that
were then combined with EPIONCHO output on infection and disease
projections (Turner et al., 2014a). By contrast, Coffeng et al. (2013a), com-
bined financial cost data from APOC, beneficiary governments and
nongovernmental organizations with ONCHOSIM output to evaluate
the APOC programme as a whole between 1995 and 2010, and then extrap-
olate forward to 2015. For the alternative intervention strategies, for which
cost data are not yet be available, such as MDA with moxidectin (Turner
et al., 2015a) or treatment with doxycycline (Walker et al., 2012a), compar-
ative economic evaluations have been undertaken by expressing their cost
relative to the de facto strategy of ivermectin MDA.

6.3 The economics of elimination and eradication

Traditional cost-effectiveness analyses balance the effectiveness of an interven-
tion in preventing disease with its cost, weighting costs and health gains
incurred in the present more heavily than those incurred in the future (a pro-
cess known as discounting, Drummond et al., 1997). Before the change in
emphasis from onchocerciasis (disease) control to (infection) elimination,
this was a perfectly adequate analytical framework to use when evaluating
intervention strategies (e.g., Prost and Prescott, 1984). Now, however, and
as for many other NTDs earmarked for elimination, the emphasis of eco-
nomic evaluations is changing from the ratio of cost to effectiveness (cost-
effectiveness) to the absolute cost of an intervention and the time it takes
to achieve the desired elimination goal. For example, Turner and co-workers,
in their comparisons of biannual versus annual MDA with ivermectin (Turner
et al., 2013b) and annual or biannual MDA with ivermectin versus MDA
with moxidectin (Turner et al., 2015b), emphasized not the cost-effectiveness
of the various strategies but rather the time required to eliminate and the cost
savings that would be possible by eliminating more rapidly with more effec-
tive interventions. Such evaluations (Kim et al., 2015a) are clearly of para-
mount interest to the funders of the numerous global initiatives that aim to
eliminate NTDs and other infectious diseases (Sicuri et al., 2015).
Eradication investment cases have been put forward for a number of
NTDs, including onchocerciasis (Bailey et al., 2015; Tediosi et al., 2013).
River Blindness 319

Regarding onchocerciasis, Kim and co-workers developed control, elimina-

tion and eradication scenarios. For each scenario, the timeline when treat-
ment would be expected to stop at country level was predicted using
ONCHOSIM, and ivermectin treatment needs were predicted based on
population numbers in endemic areas, treatment coverage data, and fre-
quency of annual CDTI (Kim et al., 2015b). The control scenario would
require CDTI beyond 2045 with around 2.63 billion treatments over
2013e2045; the elimination scenario would require CDTI until 2028 in areas
where elimination is feasible, but beyond 2045 in countries with operational
challenges, requiring an estimated 1.48 billion treatments; the eradication
scenario, which was predicted to last until 2040, would necessitate around
1.3 billion treatments. Kim et al. (2015b) concluded that the eradication
scenario would be the most favourable in terms of intervention timelines
and treatment needs. This study, however, did not consider the impact of
increased frequency of ivermectin treatment, the deployment of test-and-
treat strategies, or the need for anti-wolbachial (or other macrofilaricidal)
therapies in areas coendemic with loiasis, mop-up settings or locales with
suboptimal ivermectin responses. These refinements present challenges
and opportunities for the further development of our onchocerciasis trans-
mission models which, among others, will be discussed in our next and final
section outlining directions for future work.

7. CHALLENGES AND FUTURE DIRECTIONS

The future of onchocerciasis elimination, particularly in Africa, is at a
cross-road now that APOC has closed down and control activities, fully
devolved to the national ministries of health, will have to compete with
other pressing priorities, particularly in countries that may not have yet
achieved interruption of transmission but where the disease is no longer
perceived as an important public health problem. A new overarching entity,
called ESPEN (Expanded Special Project for Elimination of Neglected
Tropical Diseases), has been created to operate between 2016 and 2020,
acting as a platform of support hosted and managed by the WHO Regional
Office for Africa (AFRO). ESPEN aims at integrating the control and
reducing the burden of the PCT diseases onchocerciasis, lymphatic filariasis,
schistosomiasis, soil-transmitted helminthiases and trachoma in the African
continent (http://www.afro.who.int/en/espen/about.html). It is antici-
pated that the project will help countries to recognize and fill gaps in
320 ~ez et al.
M.G. Bas
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domestic NTD programmes and to identify priority areas for funding to

tackle these diseases. Modelling should be able to play a crucial role in
strengthening such a platform (Bas
an ~ez et al., 2012). In this section we
discuss some of the challenges, opportunities and future research directions
faced by modelling to provide timely, robust and reliable support to this
endeavour in general and to onchocerciasis elimination in particular.
Firstly, it will be important that the contribution of modelling to support
decision-making and evaluation of progress towards ESPEN’s aims be
recognized given the invaluable contributions already made to the OCP
and APOC, discussed in this chapter, as modelling activities should be
embedded early in the process. Both EPIONCHO and ONCHOSIM
should be parameterized for the ecology of onchocerciasis transmission in
forest foci, as currently both models are calibrated with data derived from
savannah settings and their vectors. This is particularly important regarding
those (forest) areas that are coendemic with loiasis. Second, in countries and
foci that are progressing well towards the 2020e2025 elimination goals, it
will be crucial to maintain the momentum and political commitment, as
premature cessation of treatment programmes may lead to recrudescence
of transmission and ultimately the loss of the investments already made
(Kim et al., 2015b; Tekle et al., 2016). By nature of the protracted dynamics
of O. volvulus (Section 1.1), recrudescence may go unnoticed for a consider-
able period; this delay is also dependent on the diagnostic tools that may be
used to detect infection in humans and flies. Modelling can support the
interpretation of results gained through the use of alternative and comple-
mentary diagnostics in near-elimination and postelimination settings as
well as the design of transmission-assessment and surveillance surveys (see
Section 7.3). Third, in countries and foci with operational challenges (post-
conflict areas where treatment programmes are recently scaling up (Hodges
et al., 2011); zones with low geographical and therapeutic coverage and
adherence because of loiasis coendemicity (Wanji et al., 2015a, 2015b)),
or communities with suboptimal ivermectin responses and persistent trans-
mission despite long-term treatment (Frempong et al., 2016; Lamberton
et al., 2015), modelling will be essential to support implementation trials
of alternative treatment and intervention strategies.

7.1 Relationship between operational endpoints,

transmission breakpoints and stochastic fade-out
As discussed in Sections 4.1 and 4.2, the proposed magnitude of the pOT-
TIS will need to be revised in light of recent modelling work suggesting that
River Blindness 321

elimination may be reached earlier than prescribed by these provisional

operational thresholds for stopping MDA in areas of low to moderate pre-
control endemicity, but that they should be more stringent in areas with
initially high or very high endemicity (Stolk et al., 2015). Revision of these
programmatic thresholds is urgently needed for guiding countries on when
it may be safe to stop treatment. Further modelling work will be required to
better understand how the current and ultimately revised pOTTIS relate to
parasite transmission breakpoints and probabilistic elimination statements.
The modelling result that in EPIONCHO the pOTTIS is always reached
before the transmission breakpoint (regardless of initial endemicity) is partly
due to the long time required to reach elimination under the assumption of
exponentially distributed adult worm survival times. This assumption is
currently being modified (and results will be presented elsewhere; Walker
et al., unpublished data) to improve the ability of EPIONCHO to match
observed trends in CMFL and microfilarial prevalence as these indicators
decline with time after initiation of vector control (Plaisier et al., 1991a).
Currently, the pOTTIS are based on specified thresholds for the pres-
ence of infection in human and in fly populations, with the former measured
as microfilarial prevalence by skin snipping. However, the sensitivity of the
skin snip method decreases as the intensity of microfilarial infection in the
skin diminishes due to treatment and suppressed transmission. Therefore,
any pOTTIS based on detection of microfilariae by skin snips would have
to take into account the dwindling diagnostic performance of this method
(Bottomley et al., 2016), which still constitutes the gold standard for oncho-
cerciasis diagnosis. In view of these problems, the WHO has issued new
guidelines for stopping mass ivermectin administration and verifying elimi-
nation (World Health Organization, 2016). These guidelines are due to be
updated in 2020; in Section 7.3 we discuss the role that modelling could play
in informing this update.

7.2 Estimating basic and effective reproduction ratios

One of the most important quantitative indicators of the maximum poten-
tial of an infectious agent for introduction and persistence in a host popula-
tion is the basic reproduction ratio or number, R0 (Anderson and May,
1991). In dioeceous macroparasites such as O. volvulus, R0 is defined as
the number of mature female worms produced, on average, by a female
worm during her reproductive lifespan in the absence of density-dependent
constraints (the equivalent of the beginning of an epidemic in microparasites,
when nearly all the host population is susceptible). R0 > 1 represents the
322 ~ez et al.
M.G. Bas
an

threshold condition for endemic persistence of the parasite population

(Anderson and May, 1985). The usefulness of calculating this value resides
in the relationship between its magnitude and the amount (and type) of
intervention effort required. Therefore, the basic reproduction ratio has
been hailed as one of the most valuable ideas that mathematical thinking
has brought to epidemiology (Heesterbeek and Dietz, 1996). The definition
of R0 for helminths, however, can be problematic when, in addition to
regulatory, negative density-dependent processes of the type described in
Sections 2.1.1.1 and 2.1.2.1, there are facilitating, positive density-
dependent processes such as the mating probability (Section 2.1.1.2). This
is because as parasite density approaches zero, the probability of a female
worm mating (as well as of other positive feedback mechanisms that may
operate in the parasite life cycle) also approaches zero, making it difficult
to quantify the maximum potential for transmission in the ‘absence of den-
sity-dependent processes’, i.e., at very low levels of infection (Nåssell, 1976;
May, 1977). Woolhouse (1991) has proposed redefining the threshold
R0 > 1 as a necessary but not sufficient condition for endemic persistence;
an understanding of the dynamic processes taking place at low parasite den-
sities becoming essential.
Besides the mating probability, other facilitating processes have been
described in onchocerciasis, such as the probability that an ingested micro-
filaria survives the action of a well-developed cibarial (buccopharyngeal)
armature when present in some simuliid vectors (e.g., S. ochraceum s.l., S.
oyapockense s.l., S. incrustatum) in Latin American foci (Bas
an ~ez and
Ric
ardez-Esquinca, 2001). In these circumstances (not discussed in this
review as we focus on modelling transmission by S. damnosum s.l. in Africa)
the probability of a microfilaria reaching the fly’s abdomen intact increases
with the density of ingested microfilariae (Bas
an~ez et al., 2009). In addition,
Duerr and colleagues have suggested that immunosuppression may lead to
facilitated parasite establishment, with the probability that an incoming
worm establishes in the human host increasing with the density of already
established worms (Duerr et al., 2003). The net result of the combined
impact of a number of distinct positive density-dependent processes compli-
cates even further the estimation of R0.
A related metric, the effective reproduction ratio or Reff (which applies
during the course of an epidemic in microparasitic infections as the number
of susceptibles decreases) has been defined for (dioecious) macroparasites as
the average number of reproductively mature female worms that arise from a
single female worm during her reproductive lifespan in the presence of
River Blindness 323

(positive and negative) density-dependent processes acting on the parasite

~ez et al., 2009; Gambhir et al., 2015). Reff can therefore
life cycle (Bas
an
be formulated as the product of R0 times the expressions describing the
various density dependencies thought to operate on the parasite life cycle
(in a similar fashion to Reff in microparasites being equal to the product of
R0 times the (time-varying) proportion of susceptibles). It is the presence
of positive density dependencies (Allee effects) that make it possible for a
transmission breakpoint to occur. A breakpoint represents the unstable equi-
librium parasite density above which the population increases to reach a sta-
ble endemic equilibrium and below which the population decreases towards
the trivial (zero parasite density) equilibrium (Anderson and May, 1985;
May, 1977). The shape of the relationship between Reff and parasite density
is hence a humped one, crossing the value of Reff equal to 1 twice, firstly, on
the left of the maximum value (the ‘hump’) at the transmission breakpoint,
and secondly on the right of the hump, indicating the endemic state
(Churcher et al., 2006; Bas
an ~ez et al., 2009; Gambhir et al., 2015). The
maximum value of Reff (Rmax) has been discussed as a likely useful metric
of the reproductive potential of a parasite in a given environment that could
be used as a threshold-like quantity (an Rmax > 1 would still be necessary for
both the unstable and stable equilibria to exist).
Attempts to quantify R0 for O. volvulus in African savannah villages with
different vector biting rates were made by Dietz (1982) and Bas
an ~ez and
Boussinesq (1999). Figures ranged from 1.5 (for an ABR of 1000 per person
per year and endemic microfilarial prevalence of 50%) to 260 (for 175,000
bites per person per year and 98% microfilarial prevalence). The values in
~ez and Boussinesq (1999) obtained following the principles of stability
Bas
an
analysis (May, 1974) pertain to the nonage structured version of EPION-
CHO and are highly influenced by the vector biting rate (to which the
used formulation of R0 is linearly proportional). Using the host age- and
sex-structured version of EPIONCHO, Filipe et al. (2005) calculated
average R0 values across a number of villages in Cameroonian (savannah),
Guatemalan (coffee plantation) and Venezuelan (forest) endemic settings
as, respectively, 7.7 (95% CI 7.0e8.4, for an average ABR of w40,000);
7.3 (95% CI 5.6e8.9, for an ABR of w200,000) and 5.3 (95% CI 4.1e
6.5, for an ABR of w60,000).
Other attempts to calculate R0 assumed a (hypothetical) nonlinear rela-
tionship between the basic reproduction ratio and the annual biting rate and
yielded values ranging from 2 to 160e170 (Bas
an ~ez et al., 2007). Following
the effective reproduction ratio approach and for onchocerciasis in
324 ~ez et al.
M.G. Bas
an

Guatemala (transmitted by S. ochraceum s.l., with armed cibarium), Bas
an ~ez

et al. (2009) presented values of Rmax (for mated female worms) ranging
from 1.1 (for an ABR of w9000 and microfilarial prevalence of 34%) to
12.7 (for an ABR of 550,000 and microfilarial prevalence of 90%).
The great variation of the values presented above highlights the
difficulties in obtaining robust estimates of the basic and effective reproduc-
tion ratios for onchocerciasis. None of these estimates (with the exception of
those presented by Filipe et al., 2005) account for heterogeneities in
exposure and transmission and none have been obtained using the next-
generation matrix approach. According to this approach, and for anthropo-
notic vector-borne infections such as onchocerciasis, R0 values would be
proportional not to the product of the R0 from humans to vectors times
the R0 from vectors to humans but to the square root of this product
(Dobson, 2009). A better understanding of the relationship between
endemic infection prevalence and/or intensity and R0, Reff or Rmax would
be helpful for assessing the (relative) feasibility of elimination (a small, abso-
lute, value of R0 does not necessarily imply that elimination is easy, but a
scale of values calculated using the same method may provide a useful
comparator) and identifying optimal combinations of interventions, accord-
ing to setting, that may help to bring the effective reproduction ratio below
1 in the vicinity of the unstable transmission breakpoint.

7.3 Modelling the diagnostic performance of the skin snip

method and serological assays in near-elimination
scenarios
Bottomley et al. (2016) have modelled the sensitivity of skin snips in near-
elimination settings under a range of assumptions regarding the cumulative
effect of ivermectin on female worm fertility based on other modelling
studies (0% reduction, Bottomley et al., 2008; 7% per dose reduction,
Turner et al., 2014a; and 35% per dose reduction, Plaisier et al., 1995).
This study concluded that (1) the proposed surveillance period of 3e5 years
after stopping treatment is adequate as the sensitivity of this parasitological
method improves with time after the last treatment, and (2) taking four snips
instead of two (as routinely used) would substantially increase sensitivity,
particularly under the assumption of no cumulative effect of ivermectin
on female worm fertility (Bottomley et al., 2008). Under the current proto-
cols of two iliac skin snips, an observed microfilarial prevalence of 1%
(a component of the pOTTIS) would correspond to a predicted (underly-
ing) prevalence of 3e6% one year after treatment and of 1e2% 5 years after
River Blindness 325

treatment depending on the above mentioned assumptions, highlighting

that residual infection would be greater than what can be measured by
skin snipping. Future refinements to the EPIONCHO model will incorpo-
rate the sensitivity of skin snips according to this study.
The new WHO (2016) guidelines for stopping ivermectin MDA (World
Health Organization, 2016), although endorsing the use of skin snips for
monitoring progress during the treatment phase, do not recommend their
use to verify elimination, and instead focus on the use of serological assays
for the detection of human IgG4 to the O. volvulus antigen Ov16 (Lobos
et al., 1991; Lipner et al., 2006). For verification of elimination, the guide-
lines suggest a seroprevalence threshold of 0.1% in a sample of 2000 chil-
dren aged less than 10 years. In addition to the feasibility of sampling the
required number of children in the stipulated age range in endemic commu-
nities, the ability of serological assays to measure this threshold will depend
on the tests having, essentially, 100% specificity. Ongoing studies are being
conducted to evaluate the diagnostic performance of Ov16 serology under a
range of epidemiological settings, including Ov16 ELISA and the commer-
cially available SD BIOLINE Onchocerciasis IgG4 rapid diagnostic test
developed by PATH (http://sites.path.org/dx/ntd/onchocerciasis-the-
disease/onchocerciasis-point-of-care-test/). However, since the ability of
the skin snip method to act as the gold standard for any of these evaluations
declines when very low intensities of microfilarial infection are reached,
appropriate statistical modelling approaches should be used to analyze the
data in the absence of a gold standard in order to estimate sensitivity and
specificity as well as other test properties (Joseph et al., 1995; Dendukuri
et al., 2010). Additionally, the same questions investigated regarding the
pOTTIS apply here, namely, (1) what is the relationship between the pro-
posed serological threshold, transmission breakpoints and the probability
that elimination has been reached?, (2) what is the impact on the magnitude
of the operational thresholds (parasitological, serological or otherwise) of the
initial (precontrol) endemicity level and other epidemiological variables?
These questions are particularly relevant when ivermectin treatment pro-
grammes have been conducted in the absence of vector control (as is the
case in the majority of APOC projects), because original (entomological
and ecological) transmission conditions may still prevail despite profound
suppression of microfilarial densities (Duerr et al., 2011). ONCHOSIM
has been used to address some of these questions based on assumptions
regarding the parasite stage that elicits the IgG4 response to the Ov16 anti-
gen, and the sensitivity and specificity of the serological assays (unpublished
326 ~ez et al.
M.G. Bas
an

data). It is planned that EPIONCHO will use force-of-infection models

(Muench, 1959; Hens et al., 2010) to relate incidence (rate of acquisition
of incoming worms) in near-elimination scenarios to expected age seropre-
valence profiles with which to investigate size of appropriate serological
thresholds and age ranges that should be sampled to adequately power field
studies seeking to verify elimination.

7.4 Modelling hypoendemic onchocerciasis

Achieving elimination from the African continent will require the incorpo-
ration of hypoendemic onchocerciasis foci into ivermectin treatment pro-
grammes, since such foci were not included for priority ivermectin
treatment when APOC focused on the elimination of the disease as a public
health problem (concentrated in areas of meso- and hyperendemicity, Prost
et al., 1979). The identification of optimal strategies to treat these areas has
posed a number of questions that modelling can help to address as well as a
number of challenges.
Some hypoendemic areas, initially identified by the REMO methodol-
ogy (Ngoumou and Walsh, 1993; Noma et al., 2002), have revealed to
include meso- and hyperendemic communities when in-depth epidemio-
logical evaluations have been conducted (World Health Organization/
African Programme for Onchocerciasis Control, 2015). These foci of higher
endemicity could act as a source of infection throughout the area if not
adequately delineated and treated, but the converse could also apply, with
hypoendemic areas acting as a source of infection to controlled areas. The
conjecture has been examined that hypoendemic areas may not support
autochthonous transmission but rather are maintained as a result of spillover
transmission from adjacent areas of higher endemicity (Katabarwa et al.,
2010), with the conclusion that transmission is likely to be ongoing in
some of these areas (defined as those with nodule prevalence <20% and
microfilarial prevalence <40%). In reality, hypoendemic areas may encom-
pass vast remote areas where the focality of transmission is largely unknown
(Kelly-Hope et al., 2015). Those hypoendemic communities that are coen-
demic for loiasis would not qualify for ivermectin MDA given that the risks
of SAEs in coinfected patients with high L. loa microfilaraemia outweigh the
benefits, as discussed in Section 5. In these areas, test-and-treat protocols are
being developed, field tested and modelled using ONCHOSIM (unpub-
lished data). Key questions to be investigated by EPIONCHO and
ONCHOSIM include how best to implement alternative treatment strate-
gies, particularly anti-wolbachial therapies in these loiasis coendemic areas, as
River Blindness 327

well as what is their epidemiological impact and cost effectiveness. To

address these issues, it will be essential, on the one hand, to develop an in-
dividual-based analogue of EPIONCHO (which will remain fundamentally
distinct from ONCHOSIM, not least because this analogue would not
model individual parasites) with which to explore test-and-treat, patient-
focused strategies. On the other hand, it will be equally important to
parameterize ONCHOSIM to capture the (protracted) dynamics of the
macrofilaricidal effect of anti-wolbachial therapies such as doxycycline
(Walker et al., 2015). This would allow continuation of the approach and
philosophy of using multiple models to inform the design and optimization
of interventions strategies. Hypoendemic areas not located within areas of
onchocerciasiseloiasis coendemicity may also require alternative test-and-
treat strategies or other tailored and cost-effective approaches (Kelly-Hope
et al., 2015; Kim et al., 2015b).
Among the challenges faced when modelling hypoendemic areas are that
current frameworks do not model well areas of low initial infection preva-
lence. Under this scenario, model simulations tend to predict lack of
endemic persistence. This result is more pronounced in ONCHOSIM (in
which modelled population sizes are small, individual host heterogeneity
in exposure is included and (negative) density dependence mechanisms
are scarcer) but also occurs with EPIONCHO. The latter includes a greater
number of density-dependent regulatory (stabilizing) mechanisms as well as
age- and sex-specific exposure, but does not capture individual heterogene-
ity in exposure to vector biting. As pointed out by Churcher et al. (2005),
the interplay between heterogeneity (reflected in parasite overdispersion)
and density-dependent processes will have important implications for the
dynamics of introduction and persistence of the parasitic infection. One
way by which stability and endemic persistence of infection increases is
through the ‘rescue effects’ that result from coupling populations so that
between-patch transmission processes act to reinfect patches where the
disease cannot maintain itself or has been locally eliminated (Hagenaars
et al., 2004). In a more programmatic context this phenomenon is referred
to as ‘cross-border’ issues.

7.5 Spatial models of onchocerciasis transmission

Spatial heterogeneity is not included in either EPIONCHO or ONCHO-
SIM; each model considers closed populations, epidemiologically isolated
from other populations. This may not be so crucial when investigating sin-
gle hypothetical scenarios, but it will become increasingly important when
328 ~ez et al.
M.G. Bas
an

modelling more realistically times to elimination within and between

transmission zones. For other helminthiases such as schistosomiasis, models
representing a network of villages allowing for transport of parasites and
hosts between villages have shown that transmission can be sustained
regionally throughout a group of interconnected villages even when indi-
vidual-village conditions would not support endemicity (Gurarie and Seto,
2009).
The development of patch or spatially structured onchocerciasis models
is a very important avenue of research that would permit investigation of
infection persistence in very small but interconnected village networks,
such as those in the Amazonian focus (Botto et al., 2011, 2016), as well as
the risk of infection recrudescence being seeded by imported infections
from foci of ongoing transmission. These models may be informed by
genetic data on relatedness of worms in different transmission foci or other
data on the movement of people and vectors, and would also help to under-
stand the potential spread of suboptimal ivermectin responses. This would
also require the development of genetically structured or quantitative
trait-structured models to capture effects of differentially responding worms
and hosts to ivermectin treatment, which might help to inform optimum
strategies in foci where some communities remain stubbornly resilient to
current interventions despite long-term and high-coverage treatment
(Frempong et al., 2016).

8. CONCLUSIONS
In this chapter we have reviewed the two onchocerciasis models that
have joined forces under the umbrella of the NTD Modelling Consortium
to evaluate progress towards the WHO elimination goals and to investigate
how this progress can be accelerated. We have discussed the modelling of
current and alternative/complementary intervention strategies but many
challenges and opportunities still remain both from methodological and
from programmatic perspectives. We reiterate the plea made in an earlier
review of models for human helminthiases (Bas
an ~ez et al., 2012) that prog-
ress on both fronts can only be achieved through a continuous dialogue be-
tween quantitative epidemiologists and between these and those
implementing control programmes to fully realize the potential of models
as decision-support tools and to fully embed these into control and elimina-
tion strategies for NTDs in general and onchocerciasis in particular.
River Blindness 329

ACKNOWLEDGEMENTS
The authors of this paper gratefully acknowledge funding of the NTD Modelling Con-
sortium by the Bill and Melinda Gates Foundation in partnership with the Task Force for
Global Health. MGB and MW also acknowledge support from the Wellcome Trust.
MGB thanks the Medical Research Council.

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