1377
CLINICAL PRACTICE
Safety of and compliance with community-based ivermectin therapy
In a study of the safety, acceptability, and efficacy of ivermectin for community-based mass treatment of onchocerciasis, the drug was issued twice, one year apart, to the population of a rubber plantation (14000 people) in Liberia, where over 80% of the adults have Onchocerca volvulus infection. The plantation microfilarial load in a sample of adults was reduced by 86% 6 months after initial treatment and by 78% after 1 year. Compliance was 97% with each round of treatment. After the initial treatment of 7699 people, 101 (1·3%) had moderate adverse reactions. After re-treatment only 37 (0·5%) people had moderate adverse reactions. No ivermectin-related death or severe adverse reactions occurred. The data show that community-based treatment with ivermectin is well accepted and effective in reducing microfilarial loads. Ivermectin is likely to provide the first realistic means of chemotherapy-based control of onchocerciasis on a mass scale.
Introduction Onchocerciasis is endemic in large areas of Africa and Latin America, where over 175 million people have the infection1 and another 85 million are at risk of the disease. 3-4 million infected persons have onchocercal skin disease, and almost 1 million are visually impaired because of onchocerciasis. Ivermectin is the first drug to show promise as being suitable mass treatment of onchocerciasis. for Preregistration studies suggested that an annual dose of 150 µg/kg ivermectin is the best dose for safe and effective reduction of the microfilarial load.2-5 Because of the drug’s apparent efficacy and relative safety, community-based
therapy may become the first-line of treatment for controlling onchocerciasis.6 We report on a trial of community-based distribution of ivermectin that was designed to identify any as yet unrecognised adverse effects of the drug and to determine the efficacy and acceptability of mass distribution. ivermectin
Methods and
subjects
Distribution of ivermectin Ivermectin
given during September, October, and same three months in 1988 to people living on the Liberian Agricultural Company (LAC) rubber plantation in the rain forest area of Liberia. The population was composed of individuals from numerous Liberian tribes as well as a few expatriates. The study protocol was reviewed and approved by the appropriate committees at the Johns Hopkins School of Medicine, the Liberian Institute for Biological Research, and the World Health Organisation. Ivermectin was given out to those who agreed to treatment during a house-by-house census in each camp, except to groups deemed to be ineligible for treatment (table i). The dose given was 150 Ilgjkg. 3 days after ivermectin was issued, the household was visited again, specifically to find out whether adverse reactions had occurred. Severe reactions were defined as those causing death or permanent incapacity, or those that were life threatening. Moderate was
November, 1987, and in the
Approximately
ADDRESSES: Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, (M. Pacqué, MD, B Munoz, MS, H. R. Taylor, MD); Division of Geographic Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (B. M Greene, MD, A. T. White, MD); and of
Pathology, George Washington University Washington, DC, USA (Z Dukuly, MD). Correspondence to Dr H. Taylor, Johns Hopkins Hospital, 116 Wilmer Building, Baltimore, Maryland 21205, USA. Department Medical
Center,
’
1378
TABLE|—TREATMENT STATUS OF PLANTATION POPULATION IN 1987 AND 1988
TABLE II-MICROFILARIAL LOAD FOR ALL INHABITANTS OFTHE SAMPLE CAMPS (MFL) AND ADULT POPULATION (PMFL), AND MEAN MICROFILARIAL DENSITY (MMFD) OF TREATED COHORT
*Data for those with only 6-month
*Breastfeedmg a child †% of eligible
well as into and out of the plantation. 34% of the women and 31 % of the men present in 1987 had left the plantation within the next year.
less than 3 months of age
adverse reactions were defined as those that would prevent the person from working or carrying out usual daily activities.
Collection of skin
During
the first
snips
treatment
round, skin snips
were
taken from
everyone living in a representative sample of five camps and from all children aged 5 to 11 in every camp. In May, 1988, snips were taken again from people living in the sample camps. During the second treatment
round, snips
were
follow-up snips given separately
take from those in the five
sample
camps and from those people who had originally lived there but who had now moved elsewhere on the plantation. Skin snips were taken from the calf of each leg and from the skin over each iliac crest with a 2 mm Castroviejo sclerocorneal punch, placed in tissue culture medium, and incubated overnight at room temperature. Microfilariae seen with an inverted microscope were counted, then positive snips were weighed on an electronic scale. For each person the geometric mean of four snips per person was used to calculate the microfilarial load (MFL), which was expressed as microfilariae per mg of skin. The plantation microfilarial load (PMFL) is the microfilarial load for all subjects aged 20 years and older living in the sample camps. The mean microfilarial density (mean of MFL for all skin-snip-positive people) gives a measure of microfilarial burden in infected subjects.
Surveillance system and monitoring of health services To detect severe delayed adverse reactions physician’s assistants visited every camp every fortnight from a month before each treatment round until a month after completion of distribution of the ivermectin. From January, 1988, to August, 1988, the camps were visited monthly. During visits the physician’s assistants checked whether anyone had died or moved, or whether any pregnant women had given birth or miscarried since the last visit. For any reported death "verbal necropsy" (probing cause of death by questionnaire) was conducted with a close family member or friend .7 Records of the plantation’s 50-bed hospital were checked to monitor the occurrence of possible adverse reactions. In 1988 some reports8,9 suggested that chest pain, haematoma, or bleeding might in some way be linked to ivermectin, so during the second treatment round, staff at the plantation’s mobile clinic specifically made a note of these symptoms.
Treatment-acceptability Of the 13 704 people living on the plantation in 1987, 7956 (58%) were eligible for treatment; of these, 7699 or 97% (56% of the total population) were treated (table I). In 1988 8348 (60%) of the 13 977 living on the plantation were eligible for treatment, and of these 8062 (97%) were treated. Of the 257 people who refused treatment in 1987, 99 (73% of those who were still eligible) accepted treatment in 1988. The rate of treatment refusals (6-5%) in the five sample camps (where skin biopsies were done) was higher than that (1-6%) in other camps (p < 0-001). There was no significant difference between men and women in refusal rates (2-5% vs 1-9%). In 1987, 853 women were excluded from treatment because of pregnancy or lactation. In 1988, 576 of these women were still present on the plantation; 425 (74%) of these received ivermectin (93% of those eligible), and 102 women (18%) were again excluded from treatment because of either lactation or further pregnancy.
Intensity of skin microfilarial load The impact of ivermectin on skin microfilarial (mf) concentrations was monitored in the five sample camps, at which 8% of the total population lived. These camps closely resembled the rest of the plantation in age and sex structure.
b
months
12
U
6
12
months
Results
Population characteristics The
13 704 in 1987 and 13 977 in 1988 In both years, the mean age of the population was 19 years. During the year between the drug-distribution rounds there was considerable migration between camps as census count was
(table 1).
Microfilarial load in sample population (mf/mg skin ±95% 6 and 12 months confidence limits) before intervention and at after treatment.
1379
TABLE III-MODERATE ADVERSE REACTIONS SEEN AT PLANTATION HOSPITAL AND DURING DAY 3 FOLLOW-UP -
treatment; a 35-year-old man who died from cerebral malaria 7 months after treatment; and a 35-year-old man who was killed by lightning 8 months after treatment.
Adverse reactions reported in camps and at LAC
The microfilarial load (MFL) for the inhabitants of the sample camps was 2-2 mf/mg skin before intervention (table II). At 6 months, there was a 68% reduction (0-71 mf/mg) and at 12 months a 52% reduction (1-05 mf/mg). The overall plantation microfilarial load was 5-29 mf/mg skin before intervention, 1-30 mf/mg skin at 6 months (76% reduction), and 1-97 mf/mg skin at 12 months (63% reduction). The mean microfilarial density for those people who had received ivermectin dropped from 5-25 mf/mg skin before treatment to 0.71 mf/mg skin at 6 months (86% reduction), and to 1-18 mf/mg skin at 12 months (78% reduction) after treatment. The pretreatment microfilarial load of those who were treated was significantly higher than that of the untreated cohort (see figure). The untreated cohort was composed
mainly of people ineligible for treatment, and their microfilarial load did not change significantly over time. The microfilarial load of people moving into the plantation was similar to the pretreatment microfilarial load of the initial population at the sample camps. Plantation- wide surveillance
During the 13 months of surveillance from August, 1987, 1988,32 deaths were recorded, 17 of these among untreated children (6 infants, 9 children aged 1 to 4, and 2 children aged 5-11). Of the 15 deaths recorded in adults, 4 occurred before ivermectin distribution and 3 in adults who had not been treated (1 refused treatment, 1 was pregnant, and 1 was absent on the day of treatment). 8 deaths occurred in people who had received ivermectin, but none could be attributed to ivermectin: a 39-year-old man who died 14 days after treatment (the exact cause of death is unclear but unlikely to be due to ivermectin since he died in his sleep after being on an alcoholic binge for several days); a 50-year-old man who died from pulmonary tuberculosis 42 days after ivermectin treatment; a 48-year-old man who died from intestinal obstruction 44 days after treatment; a 37-year-old man who died from meningitis 130 days after treatment; a 60-year-old man who died from a skull fracture after a truck accident 147 days after treatment; a 55-year-old man with chronic asthma and cardiomyopathy who died with atrial fibrillation and heart failure 7 months after to August,
hospital
During the day 3 follow-up after the first treatment round 28 persons with moderately severe complaints were detected and examined. During the day 3 follow-up after the second treatment round only 16 people had moderately severe reactions. After the first treatment round, an additional 73 people presented to the hospital as outpatients with complaints that were associated with ivermectin treatment, whereas only 21 did so after the second treatment round (table III). Most complaints were of oedema and pruritus. Nobody complained of severe dizziness or orthostatic hypotension. After the first treatment round only 2 people (men) were admitted to hospital, one for severe pruritus with excoriation that became infected, and another with lower limb swelling.9 No-one needed hospital admission after the second treatment round. Among those retreated in 1988 3-4 people per thousand re-treated had complaints, compared with 6-2 per thousand treated for the first time in 1988. The overall rate during the first treatment round in 1987 was 13 per thousand. 61 people who had moderate reactions in 1987 (88% of those eligible) accepted treatment in 1988, and none of these presented with complaints at the day 3 follow-up. They were contacted 1 to 8 weeks later by a physician’s assistant, and only 13 of these reported having had even mild reactions such as mild pruritus, oedema, and body pain; the remaining 48 had no reactions at all. Mild and minimum reactions were more common and, although not specifically recorded, occurred in approximately 25 % of people receiving the treatment for the first time, but in less than 10% of those receiving their second treatment. These mild reactions usually consisted of mild fever, pruritus, oedema, or headache. Usually these symptoms resolved spontaneously, or with acetylsalicylic acid. 2 women out of 568 seen by the mobile clinic in the period before treatment complained of chest pain. None of the 468 women seen after treatment presented with chest pain. Of the 1172 men seen before treatment, 10 complained of chest pain (8 per thousand). After treatment, the mobile team saw 982 men, 5 of whom complained of chest pain (5 per thousand), and 4 of these had received ivermectin; the pain was judged to be musculoskeletal in origin in 3 individuals and of gastric origin in the 4th. No bleeding complications" were encountered.
Monitoring of later adverse effects by use
of hospital
records
Hospital records showed an overall increase in the use of the medical facilities over the 28 months from July, 1986, to October, 1988. There was no record of hospital admission for bleeding disorders for people treated with ivermectin, and there was no significant increase in stillbirths during the period after treatment as compared with the period before treatment.
During the day 3 follow-up, people often mentioned the excretion of worms in their stools. Review of hospital laboratory records for stool examinations from July, 1987, to October, 1988, showed that the percentage of stools positive for nematodes such as Ascaris, Strongyloides, or Trichuris
1380
during the 3 months following treatment (31 %) was lower than that for the previous 3 months (39%). There was no decrease in the next 3 months, but the effect reappeared after the second round of ivermectin.
Weight changes between treatment rounds was weighed before When age was controlled for, weight change between the two treatment rounds for treated people did not differ from that for untreated people.
Everyone, except pregnant women,
treatment.
Discussion As expected, the community-based distribution of ivermectin significantly reduced the microfilaria concentrations in people treated by 78 % a year after treatment. Even though less than 60% of the population were actually treated, and despite the unexpectedly high rate of migration within the community, the overall plantation microfilarial load a year after treatment was reduced to 37% of the level before treatment. No death could be related directly to ivermectin treatment and no severe reactions were recorded. Moderate adverse reactions occurred in 13 people per thousand treated after the first treatment round and in only 3-4 per thousand receiving their second annual dose of ivermectin. In this regard, it is important to note that our definitions of moderate and severe adverse reactions differ from those used in two recent publications.11,12 Whitworth and co-workers report a combined incidence of moderate and severe adverse reactions of 4-6% during a community-based distribution of ivermectin.ll Their definition of severe is similar to what we have defined as moderate. In a smaller hospital-based report, Rothova and co-workers diagnosed severe reactions in 8 (9%) of 87 treated subjects.12 In both reports, symptoms subsided rapidly after symptomatic treatment. Re-treatment a year later of those persons who had moderate reactions with the initial dose of ivermectin did not induce further reaction. This finding supports the belief that the reactions seen with initial ivermectin treatment are of the Mazzotti type,8 related to the massive killing of microfilariae, rather than being due to idiosyncrasy or allergy. Excluding the sample camps, where the higher refusal rates can be attributed to the desire to avoid repeated skin snips, the compliance rate for re-treatment was very high (982% in eligible people). This high compliance rate and the acceptance of treatment in 1988 by the people who had refused treatment or experienced moderate adverse reactions in 1987 clearly show that ivermectin is well accepted at the community level. The drop in self-reported adverse reactions in people treated with ivermectin for the first time could indicate that these reactions are now
recognised as being self-limiting. Adult
excluded from treatment because of pregancy breastfeeding form the main reservoir for microfilariae after a single treatment round. 30% of women of childbearing age were not eligible for treatment during the initial distribution. Only 18% of those who were not treated during the first round (5 % of all women of childbearing age) were again excluded during the second treatment round. If annual mass distribution were the only means of obtaining ivermectin, after 3 years 99% of women of childbearing age should have received at least one dose and 86% should have received at least two doses of ivermectin. As shown in previous studies, microfilaria counts are still considerably below pretreatment levels 2 women or
years after a single dose of ivermectin. These data suggest that, in the long run, women of childbearing age should form only a minor reservoir for microfilariae in the community. The decrease in the number of routine stool examinations
positive for intestinal nematodes at the hospital during the months following ivermectin treatment is consistent with pervious reports11,15-17 on the efficacy of ivermectin on such parasites as Strongyloides stercoralis, Ascaris lumbricoides, and Trichuris trichiura. This additional benefit of mass treatment lasted only for a short period, probably because of reinfection. In conclusion, our findings provide reassurance that ivermectin is a safe and effective drug, easy to dispense, and very well accepted by persons at risk of onchocerciasis. Thus ivermectin becomes the first practical drug suitable for use in mass treatment campaigns against human onchocerciasis. We thank the following for their support and help: Dr P. Noel Williams, Mr Kenneth Gerhart, and the staff of the Liberian Agricultural Company; Dr Aloysius Hanson, Liberian Institute for Biomedical Research; Mr Tom Margolis, Harvard Medical School; Ms Mary Cogswell, Johns Hopkins University; and Mr James Belcher and the staff of Keene Industries. This work was supported by funds from the UNDP/Word Bank/WHO Special Programme for Research and Training in Tropical Diseases (ID 870096) and from the National Institutes of Health (ID S10-RR04060).
REFERENCES 1. Third report of the WHO Expert Committee on onchocerciasis. WHO Tech Rep Ser 1987; 752. 2. Awadzi K, Dadzie KY, Schulz-Key H, Haddock DRW, Gilles HM. Aziz MA. The chemotherapy of onchocerciasis, X. An assessment of four single dose treatment regimens of MK-933 (ivermectin) in human onchocerciasis. Ann Trop Med 1985; 79: 63-78. 3. Aziz MA, Diallo S, Diop IM, Lariviere M. Efficacy and tolerance of ivermectin in human onchocerciasis. Lancet 1982; ii: 171-73. 4. Greene BM, Taylor HR, Cupp EW, et al. Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis. N Engl J Med 1985; 313: 133-38. 5. White AT, Newland HS, Taylor HR, et al. Controlled trial and dose-finding study of ivermectin for treatment of onchocerciasis. J Infect Dis 1987; 153: 463-70. 6. Taylor HR. Onhocerciasis. A potential revolution in its treatment. Int Ophthalmol 1987; 11: 83-85. 7. Pacqué-Margolis S, Pacqué M, Dukuly Z, Boateng J, Taylor HR. Application of the verbal autopsy during a clinical trial. Soc Sci Med (in
press). 8. Homeida MA, Bagi IA, Ahalib HW, et al. Prolongation of prothrombin time with ivermectin. Lancet 1988; i: 1346-47. 9. Pacqué MC, Dukuly Z, Greene BM, et al. Community-based treatment of onchocerciasis with ivermectin: acceptability and early adverse reactions. Bull WHO 1989; 67: 721-30. 10. Pacqué MC, Muñoz B, White A, William PN, Greene BM, Taylor HR. Ivermectin and prothrombin time. Lancet 1989; i: 1140. 11. Whitworth JAG, Morgan D, Maude GH, Taylor DW. Communitybased treatment with ivermectin. Lancet 1988; ii: 97-98. 12. Rothova A, van Der Lelij A, Stilma JS, Wilson WR, Barbe RF. Side-effects of ivermectin in treatment of onchocerciasis. Lancet 1989; i: 1439-41. 13. Lariviére M, Beauvais B, Aziz M, et al. Étude en Cote-d’Ivoire (1985-1987) de l’efficacité et de la tolérance de l’ivermectine (Mectizan × ) dans l’onchocercose humaine. II. Évaluation, en vue de campagnes de masse, des effets de l’administration annuelle ou semestrielle de doses uniques orales de 100, 150 ou 200 mcg/kg. Bull Soc Pathol Exot Filiales 1989; 82: 48-57. 14. Greene BM, White AT, Newland HS, et al. Single dose therapy with ivermectin for onchocerciasis. Trans Assoc Am Phys 1987: 131-38. 15. Naquira C, Jimenez G, Guerra JG, et al. Ivermectin for human stronglyoidiasis and other intestinal helminths. Am J Trop Med Hyg 1989; 40: 304-09. 16. Greene BM, Brown KR, Taylor HR. Use of ivermectin in humans. In: Campbell WC, ed. Ivermectin and abamectin. New York: SpringerVerlag, 1989: 311-23. 17. Freedman DO, Kierdt WS, Lujan A, Nutman TB. The efficacy of ivermectin in the chemotherapy of gastrointestinal helminthiosis in humans. J Infect Dis 1989; 159: 1151-53.
CLINICAL PRACTICE
Safety of and compliance with community-based ivermectin therapy
In a study of the safety, acceptability, and efficacy of ivermectin for community-based mass treatment of onchocerciasis, the drug was issued twice, one year apart, to the population of a rubber plantation (14000 people) in Liberia, where over 80% of the adults have Onchocerca volvulus infection. The plantation microfilarial load in a sample of adults was reduced by 86% 6 months after initial treatment and by 78% after 1 year. Compliance was 97% with each round of treatment. After the initial treatment of 7699 people, 101 (1·3%) had moderate adverse reactions. After re-treatment only 37 (0·5%) people had moderate adverse reactions. No ivermectin-related death or severe adverse reactions occurred. The data show that community-based treatment with ivermectin is well accepted and effective in reducing microfilarial loads. Ivermectin is likely to provide the first realistic means of chemotherapy-based control of onchocerciasis on a mass scale.
Introduction Onchocerciasis is endemic in large areas of Africa and Latin America, where over 175 million people have the infection1 and another 85 million are at risk of the disease. 3-4 million infected persons have onchocercal skin disease, and almost 1 million are visually impaired because of onchocerciasis. Ivermectin is the first drug to show promise as being suitable mass treatment of onchocerciasis. for Preregistration studies suggested that an annual dose of 150 µg/kg ivermectin is the best dose for safe and effective reduction of the microfilarial load.2-5 Because of the drug’s apparent efficacy and relative safety, community-based
therapy may become the first-line of treatment for controlling onchocerciasis.6 We report on a trial of community-based distribution of ivermectin that was designed to identify any as yet unrecognised adverse effects of the drug and to determine the efficacy and acceptability of mass distribution. ivermectin
Methods and
subjects
Distribution of ivermectin Ivermectin
given during September, October, and same three months in 1988 to people living on the Liberian Agricultural Company (LAC) rubber plantation in the rain forest area of Liberia. The population was composed of individuals from numerous Liberian tribes as well as a few expatriates. The study protocol was reviewed and approved by the appropriate committees at the Johns Hopkins School of Medicine, the Liberian Institute for Biological Research, and the World Health Organisation. Ivermectin was given out to those who agreed to treatment during a house-by-house census in each camp, except to groups deemed to be ineligible for treatment (table i). The dose given was 150 Ilgjkg. 3 days after ivermectin was issued, the household was visited again, specifically to find out whether adverse reactions had occurred. Severe reactions were defined as those causing death or permanent incapacity, or those that were life threatening. Moderate was
November, 1987, and in the
Approximately
ADDRESSES: Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, (M. Pacqué, MD, B Munoz, MS, H. R. Taylor, MD); Division of Geographic Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (B. M Greene, MD, A. T. White, MD); and of
Pathology, George Washington University Washington, DC, USA (Z Dukuly, MD). Correspondence to Dr H. Taylor, Johns Hopkins Hospital, 116 Wilmer Building, Baltimore, Maryland 21205, USA. Department Medical
Center,
’
1378
TABLE|—TREATMENT STATUS OF PLANTATION POPULATION IN 1987 AND 1988
TABLE II-MICROFILARIAL LOAD FOR ALL INHABITANTS OFTHE SAMPLE CAMPS (MFL) AND ADULT POPULATION (PMFL), AND MEAN MICROFILARIAL DENSITY (MMFD) OF TREATED COHORT
*Data for those with only 6-month
*Breastfeedmg a child †% of eligible
well as into and out of the plantation. 34% of the women and 31 % of the men present in 1987 had left the plantation within the next year.
less than 3 months of age
adverse reactions were defined as those that would prevent the person from working or carrying out usual daily activities.
Collection of skin
During
the first
snips
treatment
round, skin snips
were
taken from
everyone living in a representative sample of five camps and from all children aged 5 to 11 in every camp. In May, 1988, snips were taken again from people living in the sample camps. During the second treatment
round, snips
were
follow-up snips given separately
take from those in the five
sample
camps and from those people who had originally lived there but who had now moved elsewhere on the plantation. Skin snips were taken from the calf of each leg and from the skin over each iliac crest with a 2 mm Castroviejo sclerocorneal punch, placed in tissue culture medium, and incubated overnight at room temperature. Microfilariae seen with an inverted microscope were counted, then positive snips were weighed on an electronic scale. For each person the geometric mean of four snips per person was used to calculate the microfilarial load (MFL), which was expressed as microfilariae per mg of skin. The plantation microfilarial load (PMFL) is the microfilarial load for all subjects aged 20 years and older living in the sample camps. The mean microfilarial density (mean of MFL for all skin-snip-positive people) gives a measure of microfilarial burden in infected subjects.
Surveillance system and monitoring of health services To detect severe delayed adverse reactions physician’s assistants visited every camp every fortnight from a month before each treatment round until a month after completion of distribution of the ivermectin. From January, 1988, to August, 1988, the camps were visited monthly. During visits the physician’s assistants checked whether anyone had died or moved, or whether any pregnant women had given birth or miscarried since the last visit. For any reported death "verbal necropsy" (probing cause of death by questionnaire) was conducted with a close family member or friend .7 Records of the plantation’s 50-bed hospital were checked to monitor the occurrence of possible adverse reactions. In 1988 some reports8,9 suggested that chest pain, haematoma, or bleeding might in some way be linked to ivermectin, so during the second treatment round, staff at the plantation’s mobile clinic specifically made a note of these symptoms.
Treatment-acceptability Of the 13 704 people living on the plantation in 1987, 7956 (58%) were eligible for treatment; of these, 7699 or 97% (56% of the total population) were treated (table I). In 1988 8348 (60%) of the 13 977 living on the plantation were eligible for treatment, and of these 8062 (97%) were treated. Of the 257 people who refused treatment in 1987, 99 (73% of those who were still eligible) accepted treatment in 1988. The rate of treatment refusals (6-5%) in the five sample camps (where skin biopsies were done) was higher than that (1-6%) in other camps (p < 0-001). There was no significant difference between men and women in refusal rates (2-5% vs 1-9%). In 1987, 853 women were excluded from treatment because of pregnancy or lactation. In 1988, 576 of these women were still present on the plantation; 425 (74%) of these received ivermectin (93% of those eligible), and 102 women (18%) were again excluded from treatment because of either lactation or further pregnancy.
Intensity of skin microfilarial load The impact of ivermectin on skin microfilarial (mf) concentrations was monitored in the five sample camps, at which 8% of the total population lived. These camps closely resembled the rest of the plantation in age and sex structure.
b
months
12
U
6
12
months
Results
Population characteristics The
13 704 in 1987 and 13 977 in 1988 In both years, the mean age of the population was 19 years. During the year between the drug-distribution rounds there was considerable migration between camps as census count was
(table 1).
Microfilarial load in sample population (mf/mg skin ±95% 6 and 12 months confidence limits) before intervention and at after treatment.
1379
TABLE III-MODERATE ADVERSE REACTIONS SEEN AT PLANTATION HOSPITAL AND DURING DAY 3 FOLLOW-UP -
treatment; a 35-year-old man who died from cerebral malaria 7 months after treatment; and a 35-year-old man who was killed by lightning 8 months after treatment.
Adverse reactions reported in camps and at LAC
The microfilarial load (MFL) for the inhabitants of the sample camps was 2-2 mf/mg skin before intervention (table II). At 6 months, there was a 68% reduction (0-71 mf/mg) and at 12 months a 52% reduction (1-05 mf/mg). The overall plantation microfilarial load was 5-29 mf/mg skin before intervention, 1-30 mf/mg skin at 6 months (76% reduction), and 1-97 mf/mg skin at 12 months (63% reduction). The mean microfilarial density for those people who had received ivermectin dropped from 5-25 mf/mg skin before treatment to 0.71 mf/mg skin at 6 months (86% reduction), and to 1-18 mf/mg skin at 12 months (78% reduction) after treatment. The pretreatment microfilarial load of those who were treated was significantly higher than that of the untreated cohort (see figure). The untreated cohort was composed
mainly of people ineligible for treatment, and their microfilarial load did not change significantly over time. The microfilarial load of people moving into the plantation was similar to the pretreatment microfilarial load of the initial population at the sample camps. Plantation- wide surveillance
During the 13 months of surveillance from August, 1987, 1988,32 deaths were recorded, 17 of these among untreated children (6 infants, 9 children aged 1 to 4, and 2 children aged 5-11). Of the 15 deaths recorded in adults, 4 occurred before ivermectin distribution and 3 in adults who had not been treated (1 refused treatment, 1 was pregnant, and 1 was absent on the day of treatment). 8 deaths occurred in people who had received ivermectin, but none could be attributed to ivermectin: a 39-year-old man who died 14 days after treatment (the exact cause of death is unclear but unlikely to be due to ivermectin since he died in his sleep after being on an alcoholic binge for several days); a 50-year-old man who died from pulmonary tuberculosis 42 days after ivermectin treatment; a 48-year-old man who died from intestinal obstruction 44 days after treatment; a 37-year-old man who died from meningitis 130 days after treatment; a 60-year-old man who died from a skull fracture after a truck accident 147 days after treatment; a 55-year-old man with chronic asthma and cardiomyopathy who died with atrial fibrillation and heart failure 7 months after to August,
hospital
During the day 3 follow-up after the first treatment round 28 persons with moderately severe complaints were detected and examined. During the day 3 follow-up after the second treatment round only 16 people had moderately severe reactions. After the first treatment round, an additional 73 people presented to the hospital as outpatients with complaints that were associated with ivermectin treatment, whereas only 21 did so after the second treatment round (table III). Most complaints were of oedema and pruritus. Nobody complained of severe dizziness or orthostatic hypotension. After the first treatment round only 2 people (men) were admitted to hospital, one for severe pruritus with excoriation that became infected, and another with lower limb swelling.9 No-one needed hospital admission after the second treatment round. Among those retreated in 1988 3-4 people per thousand re-treated had complaints, compared with 6-2 per thousand treated for the first time in 1988. The overall rate during the first treatment round in 1987 was 13 per thousand. 61 people who had moderate reactions in 1987 (88% of those eligible) accepted treatment in 1988, and none of these presented with complaints at the day 3 follow-up. They were contacted 1 to 8 weeks later by a physician’s assistant, and only 13 of these reported having had even mild reactions such as mild pruritus, oedema, and body pain; the remaining 48 had no reactions at all. Mild and minimum reactions were more common and, although not specifically recorded, occurred in approximately 25 % of people receiving the treatment for the first time, but in less than 10% of those receiving their second treatment. These mild reactions usually consisted of mild fever, pruritus, oedema, or headache. Usually these symptoms resolved spontaneously, or with acetylsalicylic acid. 2 women out of 568 seen by the mobile clinic in the period before treatment complained of chest pain. None of the 468 women seen after treatment presented with chest pain. Of the 1172 men seen before treatment, 10 complained of chest pain (8 per thousand). After treatment, the mobile team saw 982 men, 5 of whom complained of chest pain (5 per thousand), and 4 of these had received ivermectin; the pain was judged to be musculoskeletal in origin in 3 individuals and of gastric origin in the 4th. No bleeding complications" were encountered.
Monitoring of later adverse effects by use
of hospital
records
Hospital records showed an overall increase in the use of the medical facilities over the 28 months from July, 1986, to October, 1988. There was no record of hospital admission for bleeding disorders for people treated with ivermectin, and there was no significant increase in stillbirths during the period after treatment as compared with the period before treatment.
During the day 3 follow-up, people often mentioned the excretion of worms in their stools. Review of hospital laboratory records for stool examinations from July, 1987, to October, 1988, showed that the percentage of stools positive for nematodes such as Ascaris, Strongyloides, or Trichuris
1380
during the 3 months following treatment (31 %) was lower than that for the previous 3 months (39%). There was no decrease in the next 3 months, but the effect reappeared after the second round of ivermectin.
Weight changes between treatment rounds was weighed before When age was controlled for, weight change between the two treatment rounds for treated people did not differ from that for untreated people.
Everyone, except pregnant women,
treatment.
Discussion As expected, the community-based distribution of ivermectin significantly reduced the microfilaria concentrations in people treated by 78 % a year after treatment. Even though less than 60% of the population were actually treated, and despite the unexpectedly high rate of migration within the community, the overall plantation microfilarial load a year after treatment was reduced to 37% of the level before treatment. No death could be related directly to ivermectin treatment and no severe reactions were recorded. Moderate adverse reactions occurred in 13 people per thousand treated after the first treatment round and in only 3-4 per thousand receiving their second annual dose of ivermectin. In this regard, it is important to note that our definitions of moderate and severe adverse reactions differ from those used in two recent publications.11,12 Whitworth and co-workers report a combined incidence of moderate and severe adverse reactions of 4-6% during a community-based distribution of ivermectin.ll Their definition of severe is similar to what we have defined as moderate. In a smaller hospital-based report, Rothova and co-workers diagnosed severe reactions in 8 (9%) of 87 treated subjects.12 In both reports, symptoms subsided rapidly after symptomatic treatment. Re-treatment a year later of those persons who had moderate reactions with the initial dose of ivermectin did not induce further reaction. This finding supports the belief that the reactions seen with initial ivermectin treatment are of the Mazzotti type,8 related to the massive killing of microfilariae, rather than being due to idiosyncrasy or allergy. Excluding the sample camps, where the higher refusal rates can be attributed to the desire to avoid repeated skin snips, the compliance rate for re-treatment was very high (982% in eligible people). This high compliance rate and the acceptance of treatment in 1988 by the people who had refused treatment or experienced moderate adverse reactions in 1987 clearly show that ivermectin is well accepted at the community level. The drop in self-reported adverse reactions in people treated with ivermectin for the first time could indicate that these reactions are now
recognised as being self-limiting. Adult
excluded from treatment because of pregancy breastfeeding form the main reservoir for microfilariae after a single treatment round. 30% of women of childbearing age were not eligible for treatment during the initial distribution. Only 18% of those who were not treated during the first round (5 % of all women of childbearing age) were again excluded during the second treatment round. If annual mass distribution were the only means of obtaining ivermectin, after 3 years 99% of women of childbearing age should have received at least one dose and 86% should have received at least two doses of ivermectin. As shown in previous studies, microfilaria counts are still considerably below pretreatment levels 2 women or
years after a single dose of ivermectin. These data suggest that, in the long run, women of childbearing age should form only a minor reservoir for microfilariae in the community. The decrease in the number of routine stool examinations
positive for intestinal nematodes at the hospital during the months following ivermectin treatment is consistent with pervious reports11,15-17 on the efficacy of ivermectin on such parasites as Strongyloides stercoralis, Ascaris lumbricoides, and Trichuris trichiura. This additional benefit of mass treatment lasted only for a short period, probably because of reinfection. In conclusion, our findings provide reassurance that ivermectin is a safe and effective drug, easy to dispense, and very well accepted by persons at risk of onchocerciasis. Thus ivermectin becomes the first practical drug suitable for use in mass treatment campaigns against human onchocerciasis. We thank the following for their support and help: Dr P. Noel Williams, Mr Kenneth Gerhart, and the staff of the Liberian Agricultural Company; Dr Aloysius Hanson, Liberian Institute for Biomedical Research; Mr Tom Margolis, Harvard Medical School; Ms Mary Cogswell, Johns Hopkins University; and Mr James Belcher and the staff of Keene Industries. This work was supported by funds from the UNDP/Word Bank/WHO Special Programme for Research and Training in Tropical Diseases (ID 870096) and from the National Institutes of Health (ID S10-RR04060).
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