The Unification of Prevention and Treatment for the Control of Onchocerciasis in Nigeria

 

Investigators:

 Evan Brown & Jack Cackler

 

evanb@stanford.edu       cackler@stanford.edu

(813)-951-5690              (703)-969-2544

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Introduction

            Onchocerciasis is a non-fatal infectious disease that accounts for a disproportional amount of morbidity worldwide.  It affects populations in countries ranging from Central Africa to both Central and South America, and to date it is estimated that more than 18 million individuals are infected with the disease.   Because onchocerciasis infection is so widespread and so greatly endemic, it is of critical importance to find modes by which to reduce its disease burden. This burden is currently estimated at upwards of 1 million DALYs [disability-adjusted life years][1], the loss of which can lead to a cycle of economic depression and stunted social progress.[2]  

            The morbidity associated with onchocerciasis results from two primary symptoms of infection.  The first symptom is that of onchodermatitis, an acute inflammatory reaction that results from the presence and death of Onchocerca volvulus microfilariae in the skin.  The inflammatory reaction most frequently leads to discomfort and irritation as well as discoloration of the skin.  In addition to onchodermatitis, onchocerciasis is the world’s second leading infectious cause of blindness.  Onchocerciasis-associated blindness results from ophthalmic lesions that occur as a result of localized immune reactions that inadvertently destroy host tissue and lead to keratitis.  Current estimates place the incidence of blindness as a result of onchocerciasis infection at 38,000 individuals per year, and its prevalence at 349,000 individuals worldwide.[3]

            In addition to causing an inordinate amount of morbidity, onchocerciasis is considered to be one of the many tropical diseases that is not only neglected, but has the potential to be eliminated and ultimately eradicated. [4]  It is thus of importance to identify onchocerciasis foci that can be targeted for elimination and in addition, create a strategy that can achieve that goal in the most efficient and cost effective manner possible.

Hypothesis

            The purpose of this study is to identify whether there is a correlation between the implementation of several strategies of treatment and prevention and a reduction in onchocerciasis incidence.  It is specifically thought that the combination of preventative and treatment measures [ivermectin and DEET] will cause the greatest reduction in onchocerciasis incidence.  The study will be carried out in Nigeria, a country in which onchocerciasis is endemic and yet the population is underserved.  The study sites will be the villages of Angwan Lemu, Apanda, Bakin-Kogi and Lankan.

Study Aims

            The aims of this study are as follows: 1] to determine whether the implementation of treatment and prevention strategies results in a decrease in onchocerciasis incidence; 2] to compare four different strategies utilizing ivermectin and DEET to determine differences in incidence reduction and overall efficacy; 3] to rank the four options from best to worst based on their ability to reduce onchocerciasis incidence in each Nigerian village; and 4] to determine which of the four strategies is the most cost effective procedure to implement against onchocerciasis endemics, based specifially on DALYs saved and their cost.

Background

            Onchocerciasis, also known colloquially as “river blindness,” is an infectious disease caused by the nematode Onchocerca volvulus.  It is widely prevalent throughout Central Africa and is thought to have been introduced to the Americas via the slave trade.[5]  Transmission of onchocerciasis is accomplished by a vector of the Simulium family, otherwise called the black fly or buffalo gnat.   The egg and larval stages of the simuliid life cycle are aquatic.  Larvae attach themselves to rocks and vegetation in swiftly running streams or rivers.[6]  For this reason, areas in which creeks and streams are topographically common play host to endemics of onchocerciasis.

            Infection of onchocerciasis occurs when a female simuliid feeds on human blood.  Saliva containing infective Onchocerca volvulus larvae penetrates the skin where they develop to maturity in subcutaneous tissue.  Mature worms travel from subcutaneous tissue to nodules where they participate in sexual reproduction, as humans are the definitive host for onchocerciasis.  Adult females produce upwards of 3000 eggs per day, which subsequently develop into microfilaria that remain in the subcutaneous tissue and perpetuate the infective cycle.[7]

            Onchocerciasis manifests itself through a number of different symptoms, most visibly noticeable of which are the nodules inhabited by adult worms that inhibit access to the immune system.  However the enormous amount of morbidity associated with onchocerciasis infection actually results from the presence of microfilariae and the effects they produce.  Dying microfilariae produce antigens that trigger an innate immune response that results in an acute inflammatory reaction.  Specifically in Africa, atrophy and subcutaneous lymphedema lead to the appearance of “leopard skin.”  Additionally, the immune response inadvertently attacks local tissues, causing lesions [referred to colloquially as craw-craw] that can impair function, most critically in the eyes.  It is these symptoms from which the great amount of onchocerciasis-associated morbidity is derived; 60% is attributed to onchodermatitis and 40% is attributed to blindness. [8]

            Treatment of onchocerciasis is most readily achieved by the anti-parasite medication ivermectin.  Ivermectin was found to greatly reduce if not entirely eliminate microfilariae in human onchocerciasis patients[9] while it was better tolerated, safer and more effective than the predominant treatments, particularly diethylcarbamazine [DEC] at the time.[10]  Ivermectin is additionally an important part of onchocerciasis control, because it eliminates transmission from humans to simuliid vectors.  Though there have recently been concerns about its toxicity and the possbility of resistance, ivermectin is currently the most effective treatment available for onchocerciasis infection.

            While invermectin has proven its worth as a means of treatment, few studies have taken into account thoughts of widespread preventative efforts against initial onchocerciasis infection.  Of specific interest for its ability to repel insects, specifically the simuliid vector of onchocerciasis, is the chemical compound DEET.  A previously conducted study demonstrated that DEET is up to 100% effective against simuliid bites[11], suggesting that its use in the effort to control onchocerciasis could yield high prevention efficacy.  It is thus of importance to consider the use of both ivermectin and DEET in efforts to control onchocerciasis infection.

 

Experimental Design

            In order to address the efficacy of several different approaches to onchocerciasis control  [prevention via DEET distribution, treatment via mass ivermectin distribution, both or neither], the study will compare four locations, in each of which a different strategy will be implemented.  Four villages that act as foci for onchocerciasis infection will be closely monitored and compared for differences of infection incidence.  The target locations are areas of similar population size, none of which are currently receiving treatment or control for the disease.  Precise data on onchocerciasis in each of the villages is currently unavailable; however, as infection with lymphatic filariasis correlates to onchocerciasis infection within Nigeria, its figures will be used to estimate onchocerciasis infection in each village.[12]

            Information concerning the four villages is as follows: 1] Angwan Lemu is located in north central Nigeria.  It has a population of 34,602, 40% of which is currently infected with lymphatic filariasis; 2] Apanda is located in south central Nigeria.  It has a population of 32,214, 43% of which is currently infected with lymphatic filariasis; 3] Bakin-Kogi is located in central Nigeria.  It has a population of 4,998, 27% of which is currently infected with lymphatic filariasis; 4] Lankan is located in northeast Nigeria.  It has a population of 10,796, 47% of which is currently infected with lymphatic filariasis.[13]

Figure 1. A map of Nigeria depicting the locations of the four villages involved in the study (Google Maps).

           

            Outreach within each of the four villages will be necessary in order to successfully implement the techniques ascribed for differential onchocerciasis prevention and treatment.  In order to proceed with the study it will be necessary to gain the participation of at least 60% of the population of each village in the study.  This requirement is stringent because these methods must be implemented at the community level in order to stand a chance for success.

            After the population outreach has been conducted and a viable percentage of each village has chosen to participate, the study shall be performed via the following methods.  Individuals in villages A and B will be supplied ivermectin as recommended by the World Health Organization [WHO] at the standard dosage of 150 micrograms/kg, twice a year.  This dosage is ideal because it maximizes microfilaricidal effects while minimizing the discomfort associated with drug-induced onchodermatitis.[14]  Alternatively, villages C and D will be given placebos within the same time frame.  Individuals in the sample populations of villages A and C will be provided DEET insect repellant at a concentration of 100% and instructed to spray themselves twice daily.  This is the recommended dosage because DEET is highly efficacious at 100% potency, providing twelve full hours of protection.[15]  Alternatively, individuals in villages B and D will be provided with identically packaged placebo insect repellant, i.e. water and provided with instructions for the same dosage and time frame.

            Thus the breakdown for onchocerciasis control within the four villages is as follows: A] Village A implements a strategy that combines both ivermectin treatment and DEET prevention; B] Village B implements a strategy in which only ivermectin treatment is utilized; C] Village C implements a strategy in which only DEET prevention is utilized; and D] Village D utilizes neither ivermectin nor DEET.

            In order to determine the efficacy of the afore-mentioned strategies, it is necessary to quantify the incidence of onchocerciasis infection. In order to ascertain onchocerciasis infection, a sample population of 100 individuals in each village will be subject to “skin snips” in order to determine the presence of microfilariae. The same individuals will be subject to the Mazzotti test, in which a light dose of diethylcarbamazine [DEC] is applied to the skin, to determine if itching results [and this microfilariae are present].  The results of each test will be systematically recorded, and the process will be repeated once every three months for a duration of five years.      Infection numbers within each sample population will be compared to the previously mentioned expected prevalence of onchocerciasis [specific to each village] in order to determine the number of new infections in each sample.  The results will be statistically analyzed in order to determine: 1] whether there is a significant change in the disease burden of onchocerciasis as a result of the plan implemented; and 2] whether there is a significant difference in the efficacy of the four different strategies.  The options that prove effective will then be subject to a cost analysis to determine which strategy [or strategies] are the most cost effective [as construed via DALYs saved] and could potentially be successfully implemented throughout Nigeria and more underserved onchocerciasis foci throughout the world.

Considerations           

            There are a number of external factors that must be taken into account prior to the initiation of this study.  It is of the utmost importance to obtain permission from national and local governments, who will hopefully be amenable to the possibility of reducing Nigeria’s disease burden.  A full ethical review of this study is also necessary.  Because placebos [either of ivermectin or DEET] are given to individuals in half of the study locations, participants in the study should be fully informed that they might not be receiving prevention and treatment.  This is likely not to be a problem, as individuals in these villages have agreed to participate in studies for lymphatic filariasis, even knowing they may not receive treatment.  Another major consideration is the presence of other endemic diseases within Nigeria.  Two diseases of importance are lymphatic filariasis and AIDS.  Both diseases can confound diagnosis for onchocerciasis, and may have synergistic effects.  In the event that an individual involved in the study has a case of onchocerciasis causing severe morbidity, such as keratitis, they shall immediately be given the appropriate treatment to resolve symptoms, regardless of what patient group they are in. 

 

Logistics

            Due to the nature of the proposed study, an enormous amount of preparation will have to go into its organization and execution.  The need for supplies, specifically including ivermectin, DEET products, as well as basic medical equipment required for the afore-mentioned testing, should be carefully estimated and rationed in order to achieve the goals of the study in the most cost effective manner.  These supplies will be purchased with grant money supplied purposefully for this endeavor.  It is important that any expenses related to this study come from the study itself, and not from local governments or individuals involved in the study.  Otherwise, the willingness to participate could be affected, and particularly within the realm of vector control, the reliability of the study may be altered.  Stipends for participating villages can be considered. 

            In addition to the previously assembled research team, the study will employ ten local caseworkers in each village to ensure that these studies will be continuously and diligently carried out. Not only will this provide meaningful employment for these individuals, but also it will place a friendly and personal face at the forefront of onchocerciasis treatment.  Previously conducted AIDS studies have shown that patients are more receptive to caseworkers from a similar cultural and linguistic background, and that their presence markedly increases success and reliability of the study.  The caseworkers will each be educated and trained in each of the afore-mentioned diagnostic tests, along with the proper administration of ivermectin and recognition of signs for which actual treatment should be initiated.  At the conclusion of the study, the caseworkers will be in a prime position to set up clinics in other villages to treat and prevent onchocerciasis in the most effective manner. Also at the close of the study, the majority of the remaining funds will be dedicated to the employment of a statistician and the programs needed for statistical analysis as well as determination of cost effectiveness.

Time Frame

            This study seeks to gain IRB approval by January 1, 2009.  The goal for the performance of the first diagnostic tests will be June 1, 2009.  As stated above, the study shall continue for five years, with sampling and testing occurring once every three months.  While the study itself shall conclude on June 1, 2014, it is the hope that the data will be collected and compiled by January 1, 2015.  The date of publication is set for June 1, 2015.  In total, this experiment will run seven years.

Significance

            The results of this study will have a profound impact on the manner in which onchocerciasis control is carried out in the future.  Because prevention of infection is so much preferrable to treatment, it is important to look into preventative methods by which incidence of the disease can be reduced.  It is thus the hope that this study will be able to come to a definitive conclusion concerning the combination of ivermectin and DEET distribution.  There is currently minimal available research concerning the combination of prevention and treatment for onchocerciasis, and it is the hope that, should our hypothesis prove true, this study can provide a framework from which to evaluate onchocerciasis health policy, particularly in countries for which treatment and prevention are currently not available.

            Additionally, by coordinating our effort to reduce incidence in the most efficacious manner with the quest for the most cost-effective reduction in incidence, it may be possible to broaden the areas within which prevention and treatment efforts take place.  Because so many areas endemic for onchocerciasis are economically depressed, it is of incredible importance to produce and implement strategies that utilize resources to their greatest ability at the least cost.  In the broad picture, this could help eliminate the economic and social burden that result from onchocerciasis morbidity, specifically blindness, and lead to a steady reduction in the overall drain on communities affected by onchocerciasis.  If achieved in a cost effective manner, this effort could even serve to reverse the cycle of economic depression felt by so many countries affected by onchocerciasis, and could potentially be used as a model for diagnosis, treatment, and prevention of other diseases in other localities throughout the world. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Works Cited

Aziz MA, Diallo S, Diop IM, Lariviere M, Porta M. “Efficacy and tolerance of ivermectin in       human             onchocerciasis.” Lancet. 1982 Jul 24;2(8291):171-3.

 

Boatin, B. A., Richards, F.O. Jr. “Control of Onchocerciasis.” Advanced Parasitology. 2006;        61:349-94.

 

Fradin, M. S., Day, J. F., “Comparative Efficacy of Insect Repellents against Mosquito Bites.”    New England Journal of Medicine. July 4, 2002; Volume 347:13-18.

 

Google Maps.  http://maps.google.com

 

Greene BM, Taylor HR, Cupp EW, Murphy RP, White AT, Aziz MA, Schulz-Key H, D'Anna             SA, Newland HS, Goldschmidt LP, et al. “Comparison of ivermectin and         diethylcarbamazine in the treatment of onchocerciasis.” N Engl J Med. 1985 Jul             18;313(3):133-8.

 

Hotez, P. J., et al. “Control of Neglected Tropical Diseases.” The New England Journal of            Medicine. 2007; 357:   1018-27.

 

John, D. T., Petri, W. A. Markell and Voge’s Medical Parasitology. Ed. Loren Wilson. Saunders Elsevier, Inc.; Philadelphia: 2006.

 

Mathers CD, Ezzati M, Lopez AD. “Measuring the burden of neglected tropical diseases: the      global burden of disease framework.” PLoS Negl Trop Dis. 2007 Nov 7;1(2):e114.

 

Matsuda, Brent M., et al. "Essential oil analysis and field evaluation of the citrosa plant    "Pelargonium citrosum" as a repellent against populations of Aedes mosquitoes." Journal of the American Mosquito Control Association. 1996; 12 (1): 69-74.

 

Micheal, E., Bundy, D. A. P., “Global mapping of lymphatic filariasis.” Parasitology Today;;

            Volume 13, Issue 12, December 1997,  Pages 472-476.

 

Okulicz, J. F., MD. “Onchocerciasis (River Blindness).” 22 May 2008. eMedicine from WebMD.             5 January 2007. < http://www.emedicine.com/derm/topic637.htm#section~treatment>

 

Richards Jr., FO, et. al.  “Mass ivermectin treatment for Onchocerciasis: Lack of evidence for collateral impact of transmission of Wucheria bnacrofti in areas of coendemicity”.  Filaria Journal.  2005.

 

Richards FO, Boatin B, Sauerbrey M, Sékétéli A. Control of Onchocerciasis Today: Status and Challenges. Trends Parasitol. 2001.

 

“Taxonomy and Systematics of Simuliidae.” 22 May 2008. Scratchpads: Biodiversity Online:       2005. < http://www.blackflies.info/>



[1] Boatin, B. A., Richards, F.O. Jr. “Control of Onchocerciasis.” Advanced Parasitology. 2006; 61:349-94.

[2] Hotez, P. J., et al. “Control of Neglected Tropical Diseases.” The New England Journal of Medicine. 2007; 357:             1018-27.

[3] Mathers CD, Ezzati M, Lopez AD. “Measuring the burden of neglected tropical diseases: the global burden of       disease framework.” PLoS Negl Trop Dis. 2007 Nov 7;1(2):e114.

[4] Hotez, P. J., et al. “Control of Neglected Tropical Diseases.” The New England Journal of Medicine. 2007; 357:             1018-27.

[5] John, D. T., Petri, W. A. Markell and Voge’s Medical Parasitology. Ed. Loren Wilson. Saunders Elsevier, Inc.;             Philadelphia: 2006.

[6] “Taxonomy and Systematics of Simuliidae.” 22 May 2008. Scratchpads: Biodiversity Online: 2005.

            < http://www.blackflies.info/>

[7] Okulicz, J. F., MD. “Onchocerciasis (River Blindness).” 22 May 2008. eMedicine from WebMD. 5 January 2007.            < http://www.emedicine.com/derm/topic637.htm#section~treatment>

[8] Boatin, B. A., Richards, F.O. Jr. “Control of Onchocerciasis.” Advanced Parasitology. 2006; 61:349-94.

[9] Aziz MA, Diallo S, Diop IM, Lariviere M, Porta M. “Efficacy and tolerance of ivermectin in human       onchocerciasis.” Lancet. 1982 Jul 24;2(8291):171-3.

[10] Greene BM, Taylor HR, Cupp EW, Murphy RP, White AT, Aziz MA, Schulz-Key H, D'Anna SA, Newland HS,          Goldschmidt LP, et al. “Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis.” N Engl J Med. 1985 Jul 18;313(3):133-8.

[11] Fradin, M. S., Day, J. F., “Comparative Efficacy of Insect Repellents against Mosquito Bites.” New England     Journal of Medicine. July 4, 2002; Volume 347:13-18.

 

[12] Richards FO, Boatin B, Sauerbrey M, Sékétéli A. Control of Onchocerciasis Today: Status and Challenges. Trends Parasitol. 2001.

[13] Micheal, E., Bundy, D. A. P., “Global mapping of lymphatic filariasis.” Parasitology Today;;

            Volume 13, Issue 12, December 1997,  Pages 472-476.

[14] Richards Jr., FO, et. al.  “Mass ivermectin treatment for Onchocerciasis: Lack of evidence for collateral impact of transmission of Wucheria bnacrofti in areas of coendemicity”.  Filaria Journal.  2005.

[15]  Matsuda, Brent M., et al. "Essential oil analysis and field evaluation of the citrosa plant "Pelargonium citrosum"            as a repellent against populations of Aedes mosquitoes." Journal of the American Mosquito Control Association. 1996; 12 (1): 69-74.