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Mectizan Program Notes No. 22 text only
Mectizan Donation Program is Expanded to Include Treatment of Lymphatic Filariasis
The Mectizan Donation Program, funded by Merck & Company, Inc., and now in its eleventh year, provides the drug that treats more than 20 million people each year for the debilitating parasitic disease onchocerciasis, known as river blindness. A once-yearly dose of the drug Mectizan (ivermectin, MSD) can effectively treat a disease that has had a profoundly harmful social and economic effect in sub-Saharan Africa.
Now Merck & Co., Inc. has announced a major expansion of that program. Research in collaboration with the World Health Organization (WHO) has demonstrated that Mectizan is also effective against lymphatic filariasis. In response to this finding, Merck will expand its donation within Africa for the treatment of lymphatic filariasis as well as onchocerciasis.
Lymphatic filariasis, also known as elephantiasis, is a disease for which, according to WHO, an estimated 300 million Africans are at risk and approximately 40 million infected. While lymphatic filariasis occurs throughout many parts of the world, approximately one-third of those infected live in Africa.
Lymphatic filariasis is transmitted by mosquitoes. The thread-like, parasitic filarial worms, Wuchereria bancrofti and Brugia malayi, that cause lymphatic filariasis live almost exclusively in humans. The worms lodge in the lymphatic system, that network of nodes and vessels that maintains the fluid balance in the tissues and blood and is an essential component of the body's immune system. They live for years, producing millions of immature microfilariae that circulate in the blood.
The clinical manifestations of lymphatic filariasis develop relatively slowly, so some people can have the disease for many years without even being aware of it. Some of these individuals may develop kidney damage due to blockage of the lymphatic system. Others will suffer the disfiguring enlargement of the arms, legs and genitals that is reflected in the name elephantiasis.
The decision to donate Mectizan for lymphatic filariasis in Africa was based on the fact that diethylcarbamazine, or DEC, which is commonly used to treat the disease, cannot be widely used in Africa because it can cause severe side effects in patients who also suffer from onchocerciasis or loaisis, both of which are common in sub-Saharan Africa.
While DEC alone has been used for more than 50 years to treat lymphatic filariasis, recent studies indicate that a combination of albendazole and DEC or albendazole and ivermectin is more effective, reducing microfilarial level in the blood by 99 percent. Recent studies also indicate that ivermectin alone reduces the microfilarial levels in the blood by more than 90 percent.
The World Health Organization currently recommends that lymphatic filariasis be treated with a combination of DEC plus ivermectin, DEC plus albendazole, or albendazole plus ivermectin. The WHO believes the effectiveness of these regimens makes them suitable for annual treatment designed to interrupt disease transmission and perhaps one day eliminate lymphatic filariasis altogether.
Given the medical need for ivermectin to treat lymphatic filariasis in countries where there is also onchocerciasis or loaisis, Merck decided to expand the Mectizan Donation Program beyond the treatment of onchocerciasis. This decision was made after Merck received French regulatory approval in 1999 for use of ivermectin to treat lymphatic filariasis.
Merck plans to donate Mectizan for lymphatic filariasis through the same system successfully established for treating onchocerciasis. Mectizan will be donated and delivered to institutions including non-governmental development organizations (NGDOs) and ministries of health, in countries where lymphatic filariasis as well as onchocerciasis or loaisis occur.
Eric Ottesen, of WHO's Center for Tropical Diseases, and one of the world's leading authorities on lymphatic filariasis, says that Merck's donation of Mectizan "has transformed the ways in which we now think of approaching some of the most intractable problems of public health in the developing world. The expansion of the ivermectin donation program to include lymphatic filariasis in Africa, which promises to help millions of people in some of the poorest areas of Africa, provides an outstanding example for others to follow."
Mitosath Overcomes Many Constraints
More and more local NGOs in Nigeria are combining efforts to broaden their role in the development and delivery of services in their country. One such NGO is Mission to Save the Helpless (MITOSATH), a small Nigerian NGO whose mission statement reads: "MITOSATH is committed to assisting those in need through the provision of health services and [to helping] government and communities to save and improve lives of needy rural people in Nigeria". It is a small NGO that sets ambitious goals, which are often reached and surpassed - in spite of constraints such as lack of funding and civil war.
In 1997, they successfully solicited $25,000 (2,225,000 Naira) in funding and the donation of a 4-wheel drive Toyota pickup truck. Fundraising efforts are ongoing. Working in three local government areas (LGAs) in Taraba State, MITOSATH treated 105,438 people with Mectizan in 1997. During the first half of 1998 they treated 48,440. Training of community-based distributors and local health workers is also a part of MITOSATH's ongoing program, as is rehabilitation for victims blinded by onchocerciasis.
In spite of communal clashes in Taraba State, MITOSATH successfully interrupted the fighting, and distributed a second round of treatment in Takum and Ussa LGAs in Taraba. Encouraged by Dr. Uche Amazigo of the APOC headquarters in Ouagadougou, MITOSATH made arrangements with state and local officials to cease-fire so that they could distribute the Mectizan. Their proposal was accepted by officials based on the severity of the disease in Taraba and the need for treatment. Additionally, MITOSATH is happy to report that after distribution, the fighting did not resume. MITOSATH hopes that other NGOs will be encouraged by their success story.
In addition to treatment and training activities, MITOSATH has long term plans with a view towards sustainability. They plan to work with the community to promote integration of onchocerciasis control into the primary health care system. This is the first year Taraba State received APOC support, therefore a great deal of effort was put into introducing Community Directed Treatment with Ivermectin.
Introduction of a Smaller Mectizan Tablet: Assessment of the Transition to a 3 mg Formulation
Introduction
In 1998, the changeover to a new 3 mg size Mectizan tablet began. The original 6 mg tablet had been used in onchocerciasis treatment programs since 1988 when the Mectizan Donation Program began but was being replaced, as recommended by field programs, with a half-size tablet and 500-tablet containers to facilitate operations. No longer will it be necessary to remove individual 6 mg tablets from foil envelopes and break them into halves to meet the required dose.
To evaluate the transition period to the new formulation and packaging and to detect unexpected problems, the Mectizan Donation Program developed a qualitative research protocol in the spring of 1998. It was implemented in two countries which were among the first to use 3 mg tablets: Mali where blindness is common and the disease is recognized as a relative health priority and Malawi where blindness is not common and the disease is a lesser health problem.
The Protocol
The qualitative research protocol developed by the Mectizan Donation Program involved two investigative approaches: 1) Focus group discussions in representative countries involving selected community members who had received 6 mg tablets in the past and 3 mg tablets in 1998; and 2) individual, in-depth interviews with personnel representing different administrative levels in the national onchocerciasis control program.
On average, four focus groups made up of four to ten persons were selected in each community and there were 3 communities from each country. To reduce inhibitions for frank discussion, the groups took into account the gender, age, and community status of participants. Discussion leaders followed topic guides prepared by the Mectizan Donation Program but allowed leeway to explore related areas of interest.
In-depth interviews followed discussion guides developed by the Mectizan Donation Program during a series of technical meetings. The guides for community distributors were translated into local languages and pre-tested in rural communities where distribution of both 3mg and 6 mg tablets had taken place.
Observations, Conclusions, and Recommendations
Among the large number of constructive observations, conclusions and recommendations from the Mali and Malawi studies are the following:
Stress Importance of annual Treatment
1. Perceptions of the seriousness of onchocerciasis differed considerably in Mali and Malawi. In Mali, where onchocerciasis-associated blindness is relatively common, the disease - and the importance of the Mectizan treatment program - were given a higher health priority than in Malawi, both at the community and national levels. In both countries, however, onchocerciasis, known as the "itching" or the "scratching" disease, was thought to be serious enough to interfere with earning a living. Building on the perceived importance of the disease, the importance of annual treatment with Mectizan should be a regular topic of programs of information, education, and communication organized as part of a national onchocerciasis treatment program.
Request for Bottles with Fewer Tablets
2. Overall, the 3 mg Mectizan tablets and 500-tablet packaging had a beneficial impact on treatment programs, particularly in terms of facilitating operations, especially that of dosing. The single greatest disadvantage, however, was the number of tablets in the new container, 500, which was considerably greater than needed in most communities. The excess commonly presented logistics problems in storing the unused tablets and retrieving them for use elsewhere.
Well Planned Training for Community Distributors and Communities
3. With respect to preparing health staffs and communities for the transition to 3 mg tablets, there was consensus that training community distributors should be carried out only when the tablets are in hand and soon to be used. Likewise, to preclude misunderstandings, education of the community should be completed before tablets are scheduled for distribution but not so far in advance that its relevancy is forgotten.
Eight-Week Window of Use
4. The eight-week period recommended for using the 3 mg tablets once the 500-tablet container is opened presented logistics problems for communities directing their own treatment. These problems need to be resolved before beginning a treatment cycle, for example by making arrangements to share a bottle of tablets with a nearby community or communities.
Frequent Education of Communities
5. One of the most important generalizations from the studies in Mali and Malawi is that if Mectizan treatment programs are to be sustained, more emphasis will need to be given to educating and re-educating communities, all of which are vulnerable to rumors, misinterpretations, and misunderstandings. A good example is the frequency with which Mectizan is mistaken for a contraceptive.
6. 6 mg tablets should be retrieved from the field prior to distribution of the 3 mg tablets to avoid confusion. A plan for retrieval of 6 mg tablets needs to be developed. An inventory of 6 mg tablets should be made and what is left could then be used for clinics or hospitals giving "passive treatment."
Copies of the complete reports on the evaluations of Mali and Malawi can be obtained by contacting the Mectizan Donation Program.
Onchocercal Ocular Disease
Onchocercal ocular disease (OOD) is one of the two most severe complications of chronic infection with the parasite Onchocerca volvulus, the other being dermatitis. Of some 18 million people infected with onchocerciasis, it is estimated that one million or more are visually impaired. Of these, 270,000 are completely blind.
In Africa, OOD is second to trachoma as a leading cause of infection-related blindness. Being blind in the developing world takes an enormous human toll, not only in the obvious incapacity, but also in shortened life expectancy resulting from that diminution of ability. Indeed, blindness, which is clinically defined as visual acuity of less than 3/60 in the better eye, can be shown to shorten one's life on average by 10 years.
The microfilariae of O. volvulus appear to enter the tissues of the eye in various ways, including along its nerves and directly from the blood. In general, the severity of the resulting eye disease relates not only to the intensity and the duration of the infection, but also to the local ecology of the geographical area in which the disease occurs. For example, it is recognized that the prevalence of OOD and blindness in West Africa is much lower in areas characterized as rainforest than in those considered savanna.
In the rainforest, blindness generally affects less than 2 percent of people with onchocerciasis. In savanna areas, however, blindness rates of 2-15 percent or higher are common. It appears that in these latter areas, particularly eye-invasive strains of parasite may be present. And different host-parasite transmission patterns related to the ecology of the savanna area in which the parasites occur may also contribute to the higher rates.
Although both eyes are usually affected by the disease, the extent of disability may be asymmetric. All parts of the eye are susceptible to invasion by microfilariae; and at some time in the course of OOD, living and dead microfilariae can be seen by slit lamp examination. Most often, blindness results from damage to the posterior segment of the eye, which includes the retina, choroid, chorioretina, and/or optic nerve. But the impact of the microfilariae on elements of the anterior segment of the eye -- the conjunctiva, cornea, iris, and lens -- can also impair vision.
The actual pathologic changes in the eye are believed to result from host immune responses incited by dead microfilariae. The parasitized tissues become progressively inflamed, producing such syndromes as uveitis or retinitis. Over time, chronic inflammation results in permanent scarring, which in turn can produce peripheral visual field defects, cataracts, and, of course, blindness.
Under normal conditions, the death of microfilariae in the eye is a relatively slow process, explaining the progressive nature of OOD. On the other hand, therapy with a microfilaricide like diethylcarbamazine(DEC), which rapidly kills microfilariae, can produce sudden and profound inflammation when there is heavy onchocercal infection. For safety reasons, therefore, DEC is unacceptable in community-based treatment programs where medical supervision may not be readily available.
Mectizan treatment, by contrast, inactivates and kills microfilariae slowly. During the first several days after a single dose of Mectizan, the number of microfilariae in the fluid of the anterior chamber of the eye remains unchanged or even increases temporarily. After two weeks or more, the number of microfilariae begins to fall and continues to do so for three or more months until they are completely eliminated.
Four months after a single treatment with Mectizan, the mean microfilarial load in the anterior chamber of the eye is reduced to 20 percent of the pre-treatment value. The living and dead microfilariae in the cornea decline to two and nine percent of pre-treatment levels.
In addition, unlike DEC, Mectizan appears not to precipitate or exacerbate optic neuritis in the period shortly after treatment.
Overall, available data on the impact of repeated doses of Mectizan on OOD indicate significant reduction in microfilarial loads in the eye and regression of early lesions of the anterior segment, including iridocyclitis and sclerosing keratitis. Mectizan also has a beneficial effect on onchocercal optic nerve disease and on peripheral visual field loss. Even though some posterior segment conditions like chorioretinitis do not improve with treatment, long-term therapy with Mectizan remains important in preventing their progression.
Mectizan Donation Program Status Report
As is customary in MPN, we present the current status of Mectizan treatments worldwide.
Through October 1998, 24 applications for Mectizan were approved. The majority of approved applications (21) were for tablets requested for the continuation of treatment programs in Brazil, Cameroon, Central African Republic, Chad, Democratic Republic of Congo, Ecuador, Mexico, Nigeria, the OCP, Sudan, Southern Sudan, Tanzania, and Yemen. Six approvals were for amendment applications requesting supplemental tablets with which to complete ongoing treatment cycles. Amendments were approved for programs in Central African Republic, Chad, and Nigeria. An initial application was approved for Senegal, one of the first OCP countries to assume responsibility for their Mectizan treatment programs in 1999.
It is estimated that approximately 34 million treatments will be approved in 1998.