267
Vitamin A supplementation and child survival
Previous studies of the effect of 6-monthly vitamin supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebocontrolled trial of vitamin A supplementation in the Sudan among 28 753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200 000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 I U vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8·4/1000) in the vitamin A group and 112 (7·9/1000) in the placebo group (relative risk 1·06, 95% confidence interval 0·82-1·37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of A
dying. The lack of
effect of
large-dose vitamin A supplementation mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a publichealth measure. Reducing poverty, improvements in an
on
access to adequate diets should remain the main goals to improve child survival.
sanitation, and
Introduction Vitamin A
deficiency
occurs
largely
in
developing
countries among undernourished children whose diets are limited in carotene-containing vegetables, animal products, and fat. Repeated episodes of diarrhoea and other infections interfere with absorption and increase vitamin A requirements.1 Febrile illness and especially measles may precipitate keratomalacia in subjects with depleted vitamin A stores; administration of large doses of vitamin A to children with measles reduces mortality.2-4 Children with signs of vitamin A deficiency were at a substantially higher risk of dying than were normal children.4,5However, since these studies did not completely control for socioeconomic, nutritional, and health covariates,a causal relation between vitamin A deficiency and mortality was not conclusively shown. More recently, four randomised trials of vitamin A supplementation have been conducted in areas of Asia where vitamin A deficiency is common. Two of these trials used distribution of 200 000 IU vitamin A every 6 months as treatment with conflicting results: in one there was a 34% reduction in mortality, whereas in the other there was no effect.7 In the third trial, 200 000 IU vitamin A was given
every 4 months and mortality was reduced by 30%,8 and in the fourth trial, administration of weekly supplements of 8333 IU vitamin A was associated with a 54% reduction in
mortality.99 To extend the above observations, we here report the results of a double-blind, placebo-controlled trial of vitamin A supplementation among children aged 9-72 months in the Sudan. Our objectives were: (a) to test the efficacy of large doses of vitamin A given every 6 months in reducing child mortality, morbidity, and malnutrition and (b) to identify predictors for child death, including deficient dietary intake of vitamin A.
Subjects and
methods
The study was conducted between June, 1988, and December, 1990, among children between 9 and 72 months of age in five rural
councils in northern Sudan where vitamin A deficiency was present. There are local expressions for night blindness such as "jahar", suggesting awareness of the problem among the target population. The location of the study sites allowed regular supervision from headquarters. The study was approved by the Committee on the Use of Human Subjects in Research of the Harvard University School of Public Health, the Director General of Primary Health Care of the Ministry of Health in the Sudan, and both Directors of Health for Khartoum and Central Regions. Verbal informed consent was obtained from the mothers at the time of enrolment since most were illiterate. Field work was conducted by six teams, each consisting of a supervisor, two interviewers, two anthropometrists, and a driver. All staff were experienced Ministry of Health personnel assigned to work full time on the study. Screening, baseline data collection, and administration of the first treatment were done during enrolment. Colour-coded capsules containing either 200 000 IU vitamin A and 40 IU vitamin E (vitamin A group) or 40 IU vitamin E (placebo group) were provided by Hoffman-La Roche, Basel, Switzerland. Only the manufacturer knew the contents of the capsules until after data collection and preliminary analysis of the results. After 22 months of storage, a sample of capsules of both colours was sent to the manufacturer for analysis; 15 % of the vitamin A activity had been lost. New capsules were obtained to complete the study. Each interviewer was assigned one of the colours for the duration of the study to minimise errors. Randomisation was done by household. To facilitate locating subjects in subsequent rounds, interviewers recorded identification data, addresses, and directions on colourcoded household cards that matched the colour of the trial capsule. Upon arrival at a village, the supervisor in consultation with village leaders chose a central location to carry out anthropometric measurements. Interviewers conducted a house-to-house survey beginning at the northeastern end of the village. Assignment to treatment group was achieved by the two interviewers visiting alternate households throughout the village. If the household did not include children between the ages of 9 and 72 months or the members refused to take part in the study, the interviewer went to the next household. Otherwise, the interviewer issued a unique identification number for each eligible child. ADDRESSES Harvard Institute for International Development, Cambridge (M. G Herrera, MD, P Nestel, PhD, L. Weld, PhD) and the Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (M. G. Herrera), Division of Nutrition, Ministry of Health, Khartoum, Sudan (A. El Amin, K. A. Mohamed, MD), and Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA (W. W. Fawzi, MD) Correspondence to Dr M G Herrera, Harvard Institute for International Development, 1 Eliot Street, Cambridge, MA 02138, USA.
268
Dietary, social, economic, and demographic data were recorded questionnaire. The birth date of each child was ascertained
on a
with the local Muslim calendar and the birth certificate if available. A 24 h dietary recall survey of foods containing vitamin A was done and the occurrence of diarrhoea (three or more loose or watery stools per 24 h), pyrexia, cough (present for at least 24 h), and measles during the preceding 7 days was also recorded. Mothers were carefully questioned about the presence of night blindness in the enrolled children. The interviewer, using a loupe (x 2 magnification), examined the children’s eyes for Bitot’s spots, corneal scars, and corneal ulcers. Interviewers emptied the contents of one study capsule (vitamin A or placebo) into the mouth of all non-xerophthalmic children. Mothers then took the children to the field site where they were weighed to the nearest 0.1 kg (Salter hanging scale). Height (or recumbent length for children under 85 cm) was measured to the nearest 0.1 cm with a locally made anthropometer. Questionnaires and household identification cards were checked daily by the supervisor for accuracy, consistency, and completion. The supervisor repeated the ocular examinations of all xerophthalmic subjects. If xerophthalmia was confirmed, 200 000 IU vitamin A with 40 IU vitamin E was given (also provided by Hoffman-La Roche), if the diagnosis was refuted, the child was given the appropriate study capsule. Xerophthalmic children were removed from the remainder of the study. All children were given a vitamin A capsule at the end of the study. Household surveys were repeated 6, 12, and 18 months after enrolment. At each follow-up, birth date, morbidity, dietary intake of vitamin A, and anthropometric measurements were recorded as well as symptoms associated with death when that was the outcome. Ocular examinations were repeated and study capsules were administered. Children with xerophthalmia were treated with vitamin A and not followed up further. Children who for any reason were not available were not given further trial capsules but their survival status was ascertained from family or neighbours. Supervisors attended 13% of all interviews. Senior project staff visited each team in the field once every 2 weeks to attend interviews, review questionnaires, monitor anthropometric measurements, and discuss problems. On alternate weeks the teams met with the project staff at headquarters.
Data processing and analyses Data recorded on questionnaires were entered on diskettes, and verbally cross-checked against the questionnaires. Verification programs were run after each round with the Centers for Disease Control Anthropometric Software and SPSS PC version to identify outliers and inconsistent answers; original forms were checked and transcription errors were corrected. Birth dates were converted from the Muslim to the western calendar by computer. The four dates provided by the mother were compared with the birth certificate, when available, and a final birth date was assigned when at least two of the available dates coincided within a month; a birth date could not be assigned to 12% of the children. The occurrence of diarrhoea, pyrexia, cough, and measles during the 7 days preceding each of the four surveys was used to calculate the morbidity burden by adding the number of symptoms during that time. To identify risk factors for mortality, morbidity data obtained at the initiation of each of the three periods of observation were used. Approximate vitamin A consumption was estimated from the 24 h dietary intake survey data with African and US Department of Agriculture food composition tables.1o,11 An average portion was assumed since the questionnaire established only whether or not a certain food item had been consumed during the day before the survey. The data reflect differences in consumption between subjects but should not be regarded as a precise measure of actual intake. Dietary data were collected every 6 months at the beginning of each round of observation. For analyses involving the first 6 months of observation, baseline dietary data were used; averages of baseline and round-2 data were used for analyses pertaining to the second period; averages of baseline, round-2, and round-3 data were used for analyses pertaining to the third period of observation.
printed,
Status of study cohort throughout study.
Non-compliant subjects are those who missed dose at 6 mo and/or those who missed dose at 12 mo. They had a lower mortality rate because they were at risk only during rounds 2 and 3, when overall mortality was lower.
Height-for-age and weight-for-height
Z
scores were
calculated
by reference to the National Center for Health Statistics (NCHS) standards.l2 Children who fell below - 2 Z score in height-for-age classified as stunted, those who fell below - 2 Z score in weight-for-height were classified as wasted. Sanitation was assessed only at baseline. The presence of water in the household proved to be a proxy for other sanitation-related variables such as the presence of a latrine in the home. Poverty was rated on a scale of one to four based on the quality of the dwelling and household possessions at the time of the initial survey. Treatment effects were calculated by use of relative risks (RR) with 95 % confidence intervals (CI). Mortality rates were calculated for children enrolled at baseline and alternatively for those who actually received a trial capsule in the previous round. Logistic regression and discrete time survival analyses13 were used to estimate the overall treatment effect adjusted for baseline differences and to identify predictors of mortality, including dietary vitamin A intake. Data analyses were done with SAS/PC v6.04.
were
Results There were 17 031 eligible households enrolled at baseline. 29 615 children were screened, of whom 862 (3%) were diagnosed as xerophthalmic, treated, and not followed up further (figure). Thus, 28 753 children were enrolled. 3320 children did not receive one or two of the three vitamin A or placebo capsules. Most of this non-compliant group consisted of children absent from the household at the time of follow-up, whereas others had moved away or refused to take part further. As a group, the non-compliant children tended to be from poorer households than those who continued in the study. However, there were no significant
269
TABLE I-BASELINE COMPARISONS OF NON-XEROPHTHALMIC CHILDREN
TABLE III-MORTALITY BY AGE, SEX, NUTRITIONAL STATUS, AND MORBIDITY
Data shown as placebo/vitamin A. *No deaths occurred in children 72 months.
in the placebo group (RR 1 06,95% CI 0’82-1’37) (table II). Controlling for region, study round, baseline anthropometry, baseline morbidity, sex, and all baseline differences between vitamin A and control groups did not change the results, nor did inclusion of the 8 deaths among non-compliant children. Vitamin A administration had no effect on mortality in either sex. Mortality was much higher among children under the age of 36 months, but there were no effects of supplementation on mortality within the 0-35 months, 36-71 months, and 72-and-over age-groups. Differences in mortality between vitamin A and control groups were not statistically significant within nutritional status subsets *Rated by enumerators on a scale of 1-3, tRated by enumerators on a scale of 1-4, based on characteristics of dwelling and household possessions tOwnershlp of bicycle or car. In the previous 7 days IlWasted < - 2 Z score weight/height; stunted < - 2 Z score height/age Unrts are retinol equivalents (SD)
differences between vitamin A and placebo groups in the number of non-compliant subjects or in their ages, sex, or nutritional status. At the end of the study, the survival status was known for all children originally enrolled apart from those excluded because of xerophthalmia and 167 others who could not be traced. The figure summarises the status of the cohort throughout the study.
Baseline characteristics Baseline characteristics of the sample by treatment group are shown in table I. There were no important differences between vitamin A and placebo groups in rate of xerophthalmia (2-8 vs 2-9%), vitamin A intake, age distribution, or nutritional status.
Effect of supplementation
on
mortality
During the 18 months of follow-up, there were 120 deaths
(8-4/1000) in the vitamin A group and 112 deaths (7-9/1000)
(table III). Exclusion of 24 deaths due to causes unlikely to be affected by vitamin A (motor vehicle accidents, scorpion bites, burns) did not change the above results. There were no significant differences between vitamin A and placebo groups in symptoms associated with death, although there were fewer deaths associated with shortness of breath in the vitamin A group (table IV). De-novo appearance of night blindness was reduced by about 50 % in the vitamin A group (0-53, 0,28-0,99) compared with the placebo group. Denovo incidence of Bitot’s spots was reduced by vitamin A supplements (0-89, 0°Trl °09). Dietary vitamin A irrespective of group was also associated with reduced incidence of night blindness (top quintile vs bottom quintile 0-54, 0-22-1-34) and Bitot’s spots (top quintile vs bottom
quintile 0-70, 0 51-0-96). Variables previously identified as important in bivariate analyses were included sequentially in a model designed to explain mortality. As expected, mortality was associated with age, nutritional status, morbidity, round, and region. Children who lived in the relatively privileged region 3 were more likely to survive; illness during the week before each TABLE IV-SYMPTOM-SPECIFIC MORTALITY BY TREATMENT
GROUP*
TABLE II-VITAMIN A SUPPLEMENTATION AND SURVIVAL
*Includes 140 children with xerophthalmia at round 4 tlncludes deaths among non-compliant children (3 vitamin A, 5 placebo)
*Symptoms reported by principal
supervisor-
270
TABLE V-MORTALITY RISK ASSOCIATED WITH VARIOUS FACTORS
Controlling for all other variables in the model. *Follow-up period 6-12 2 mo (round 2) tResidence
in EI Jaeli, region where mortality was lower tAge at beginning of each round (increments of 12 mo) §No of symptoms (diarrhoea, pyrexia, cough, measles) in week preceding each
round.
DWater supply in house Poverty= rating of household by enumerator DietvitA=dietary mtake of vitamin A (Increments of 100 retinol equivalent) Supplementation = administration of 200 000 IU vitamin A every 6 mo.
round of observation children with lower
associated with the risk of dying; weight-for-height or height-for-age were at a much higher risk of death than were normal children; and low dietary intake of vitamin A significantly increased risk of mortality even when the model included round, region, age, anthropometry, morbidity, poverty, sanitation, and treatment with vitamin A (table v). was
Discussion The results show that in Sudan, supplements of 200 000 IU vitamin A taken every 6 months had some protective effect on incidence of eye signs and symptoms of vitamin A deficiency but did not lower child mortality. The lack of effect on child mortality accords with the findings of the Andra Pradesh study where 200 000 IU vitamin A were also given every 6 months.7 By contrast, distribution of 200 000 IU vitamin A every 4 or 6 months in Nepal8 and Indonesia6 resulted in a 30-34% reduction in child mortality. Our findings also differed from those of the study in Tamil Nadu in southern India where the weekly distribution of 8333 IU vitamin A was associated with a 54% reduction in child
mortality.9 To understand these apparently conflicting outcomes, it is necessary to keep in mind the wide differences in the settings where the studies were conducted, the diversity of treatment protocols, and the lack of precise information about severity of vitamin A deficiency in the study populations. The administration of 200 000 IU vitamin A every 6 months may have been inadequate to redress severe depletion. Of the three studies that have used this treatment regimen, only the one in Indonesia’where the baseline prevalence of eye signs was the lowest, showed that vitamin A supplementation reduced mortality. In the Sudan study, the modest effect of supplementation in preventing de-novo appearance of eye signs of vitamin A deficiency supports the hypothesis that vitamin A every 6 months is inadequate. A smaller but more frequent intake of the vitamin in an adequate diet or by administration of weekly supplements, as in the Tamil Nadu trial or through food fortification/4 may be more effective than the administration of massive doses 6 months apart.15,16 In Tamil Nadu, children with xerophthalmia were treated with 200 000 IU vitamin A and then assigned randomly to either vitamin A or placebo groups: the weekly administration of the small dose of vitamin A proved effective in reducing mortality even
finding suggests that the 200 000 IU dose given as treatment was insufficient to protect children who did not receive the weekly supplement thereafter. Vitamin A supplementation may have failed to lower mortality because deficiency was not severe enough. Our study included households of differing socioeconomic status and vitamin A intake; there was, however, no indication that supplementation reduced mortality even among the lowest quintile of vitamin A intake or among the poorest households. Comparison of baseline rates of xerophthalmia across studies does not suggest that the severity of vitamin A deficiency influenced the efficacy of supplementation. Tamil Nadu had the highest rate followed by, in descending order, Hyderabad, Nepal, Sudan, and Indonesia. However, eye signs of vitamin A deficiency are an imprecise endpoint: they were used because other practical and more valid methods were not available. The effect of vitamin A supplementation may be especially effective among deficient subjects with lifethreatening infections. By, comparison across studies, mortality rates in the control groups were higher in the three sites where vitamin A supplements were effective than where vitamin A had no effect. This observation is compatible with a protective effect of vitamin A in life-threatening infections among deficient subjects.17 Vitamin A reduces case-fatality in severe measles2-4 and seems to lower mortality without altering the incidence of infectious disease.9,17 Diet and intestinal parasite infestation may have influenced the effect of vitamin A supplementation on mortality. Dietary fat affects absorption of vitamin A and thus may modify the effects of the vitamin on child survival. Other nutrient deficits (eg, zinc) may render subjects unresponsive to vitamin A supplementation;"I,19 such effects have not been assessed by any of the randomised trials to date. Further work is needed to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Factors such as frequency of supplementation, severity of vitamin A deficiency, incidence and severity of specific infectious diseases, and concurrent nutrient deficits need to be investigated. Also, the possiblity that vitamin A supplements are protective against certain pathogens but not against others deserves attention. We have also shown that various risk factors contributed independently to the risk of death. That mortality was lower during the second and even lower during the third 6-month period, irrespective of the capsule received, reflects both the ageing of the cohort and a reduction in the number of subjects at most risk, since they had died during preceding observation periods. Low dietary intake of vitamin A significantly increased the risk of mortality (controlling for morbidity, anthropometry, round, region, poverty, and sanitation), suggesting that ingestion of small but frequent amounts of vitamin A was more effective in reducing mortality than was administration of large doses of the vitamin at 6-monthly intervals. Such a conclusion is supported by the results of the Tamil Nadu study and those of a monosodium glutamate fortification programme in Indonesia.9,14 On the other hand, it is important to keep in mind that the association between dietary vitamin A and mortality in our study, though robust enough to persist after controlling for all the factors tested in table v could still be confounded by household characteristics that were not measured. among this subset of the cohort. This
271
In conclusion, large doses of vitamin A delivered every 6 months may not be sufficient to ameliorate deficiency in some settings, perhaps as a result of other dietary deficits. Conversely, the differences in outcomes between trials may be related to severity of deprivation and burden of disease: mortality rates were higher at the sites where vitamin A was effective. Further investigation of factors that modify the efficacy of vitamin A supplementation on mortality is needed to guide policy formulation. In accordance with findings in other developing countries, Sudanese children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. There were differences in mortality associated with dietary intake of vitamin A even after controlling for indicators of socioeconomic status and sanitary conditions of the home. A reduction in poverty, improvements in sanitation, and access to adequate diets should remain the goals of child survival efforts. Assuring adequate levels of intake of vitamin A by increasing dietary intake through fortification of staple foods or by providing small supplementary doses frequently may be more effective in some settings than distribution of massive doses of vitamin A. Improvement of vitamin A intake by whatever possible and effective means, including periodic distribution of large doses, continues to be of high priority in areas where the deficiency is prevalent and nutritional blindness a common and tragic occurrence.
Center for Health Statistics, November 1977. (DHEW
13.
14.
publication [PHS] 78-1650). Singer JD, Willett JB. Modeling the days of our lives: using survival analysis when designing and analyzing longitudinal studies of duration and the timing of events. Psychol Bull 1991; 110: 268-90. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988;
48: 1271-76. 15. Swaminathan MC, Susheela TP, Thimmayamma BVS. Field prophylactic trial with a single annual oral massive dose of vitamin A. Am J Clin Nutr 1970; 23: 119-22. 16. Gopalan C. Combating vitamin A deficiency-need for a revised strategy. In: Recent trends in nutrition. Proceedings of First International Symposium of the Nutrition Foundation of India. Oxford: Oxford University Press, 1991 (prefatory chapter). 17. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC. Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. Am J Clin Nutr 1991; 54: 568-77. 18. Glover J. Factors affecting vitamin A transport in animals and man. Proc Nutr Soc 1983; 42: 19-30. 19. Udomkesmalee E, Dhanamitta S, Sirisinha S, et al. Effect of vitamin A and zinc supplementation on the nutriture of children in Northeast Thailand. Am J Clin Nutr 1992; 56: 50-57.
SHORT REPORTS Simian immunodeficiency virus needlestick accident in a laboratory worker
We thank Dr Walter Willett and Dr John Orav for valuable advice throughout the study, Dr El Fatih El Samani for help in the planning and early phases of the project, the USAID mission in Khartoum for their invaluable support, the field staff whose hard work made the study possible, Dr Elizabeth Allred for her assistance in data management, Hoffinan-La Roche Task Force Sight and Life Program for provision of vitamin capsules and for conducting the assays, and Ms Jill Arnold for her assistance in the preparation of the manuscript.
This study was carried out under cooperative agreement No. DAN-0045G-SS-6067 of the Office of Nutrition, US Agency for International Development (USAID), Washington, DC, and the Harvard Institute for International Development, Cambridge, MA, USA, and the Division of Nutrition, Ministry of Health, Khartoum, Sudan.
REFERENCES 1. Sivakumar B, Reddy V. Absorption of labelled vitamin A in children during infection. Br J Nutr 1972; 27: 299-304. 2. Barclay AJG, Foster A, Sommer A. Vitamin A supplements and mortality related to measles: a randomized clinical trial. BMJ 1987;
294: 294-96. Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990; 323: 160-64. 4. Sommer A, Hussaini G, Tarwotjo I, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983; ii: 585-88. 5. Sommer A. Mortality associated with mild, untreated xerophthalmia. Trans Am Ophth Soc 1983; 81: 825-53. 6. Sommer A, Djunaedi E, Loeden AA, et al. Impact of vitamin A supplementation on childhood mortality. Lancet 1986; i: 1169-73. 7. Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990; 336: 1342-45. 8. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; 338: 67-71. 9. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35. 10. United States Department of Health, Education and Welfare, Public Health Service, and the Food Composition and Planning Branch of the Food and Agricultural Organization. Food composition tables for use in Africa. Rome: FAO, 1968. 11. United States Department of Agriculture, Agricultural Research Service. Composition of foods, Agriculture Handbook No. 8-1. Washington, 3.
Hussey GD,
DC, USDA, November, 1976. 12. Hamill PVV, Drizd TA, Johnson CL, et al. NCHS growth curves for children birth-18 years United States. Hyattsville, MD: National
The macaque monkey infected with simian immunodeficiency virus (SIV) is an animal model of the acquired immunodeficiency syndrome. We investigated a laboratory worker who was exposed by needlestick accident to blood from an SIVinfected macaque. Seroreactivity to SIV developed within 3 months of exposure, with antibody titres peaking from the third to the fifth month and declining thereafter. Polymerase chain reaction for SIV sequences and cultures of peripheral-blood mononuclear cells failed to show infection. Inoculation of an SIV-negative monkey with blood from the worker did not cause infection. Animal-care and laboratory workers should adhere strictly to recommended procedures to avoid accidental exposures when working with SIV-infected animals or
specimens.
virus (SIV) infection of valuable animal model for the study of the acquired immunodeficiency syndrome (AIDS).12 There is a potential risk that human beings working in research laboratories may be exposed to SIV.3 To date, however, no SIV infection in human beings has been reported. We Simian
immunodeficiency
macaques is
a
Vitamin A supplementation and child survival
Previous studies of the effect of 6-monthly vitamin supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebocontrolled trial of vitamin A supplementation in the Sudan among 28 753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200 000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 I U vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8·4/1000) in the vitamin A group and 112 (7·9/1000) in the placebo group (relative risk 1·06, 95% confidence interval 0·82-1·37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of A
dying. The lack of
effect of
large-dose vitamin A supplementation mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a publichealth measure. Reducing poverty, improvements in an
on
access to adequate diets should remain the main goals to improve child survival.
sanitation, and
Introduction Vitamin A
deficiency
occurs
largely
in
developing
countries among undernourished children whose diets are limited in carotene-containing vegetables, animal products, and fat. Repeated episodes of diarrhoea and other infections interfere with absorption and increase vitamin A requirements.1 Febrile illness and especially measles may precipitate keratomalacia in subjects with depleted vitamin A stores; administration of large doses of vitamin A to children with measles reduces mortality.2-4 Children with signs of vitamin A deficiency were at a substantially higher risk of dying than were normal children.4,5However, since these studies did not completely control for socioeconomic, nutritional, and health covariates,a causal relation between vitamin A deficiency and mortality was not conclusively shown. More recently, four randomised trials of vitamin A supplementation have been conducted in areas of Asia where vitamin A deficiency is common. Two of these trials used distribution of 200 000 IU vitamin A every 6 months as treatment with conflicting results: in one there was a 34% reduction in mortality, whereas in the other there was no effect.7 In the third trial, 200 000 IU vitamin A was given
every 4 months and mortality was reduced by 30%,8 and in the fourth trial, administration of weekly supplements of 8333 IU vitamin A was associated with a 54% reduction in
mortality.99 To extend the above observations, we here report the results of a double-blind, placebo-controlled trial of vitamin A supplementation among children aged 9-72 months in the Sudan. Our objectives were: (a) to test the efficacy of large doses of vitamin A given every 6 months in reducing child mortality, morbidity, and malnutrition and (b) to identify predictors for child death, including deficient dietary intake of vitamin A.
Subjects and
methods
The study was conducted between June, 1988, and December, 1990, among children between 9 and 72 months of age in five rural
councils in northern Sudan where vitamin A deficiency was present. There are local expressions for night blindness such as "jahar", suggesting awareness of the problem among the target population. The location of the study sites allowed regular supervision from headquarters. The study was approved by the Committee on the Use of Human Subjects in Research of the Harvard University School of Public Health, the Director General of Primary Health Care of the Ministry of Health in the Sudan, and both Directors of Health for Khartoum and Central Regions. Verbal informed consent was obtained from the mothers at the time of enrolment since most were illiterate. Field work was conducted by six teams, each consisting of a supervisor, two interviewers, two anthropometrists, and a driver. All staff were experienced Ministry of Health personnel assigned to work full time on the study. Screening, baseline data collection, and administration of the first treatment were done during enrolment. Colour-coded capsules containing either 200 000 IU vitamin A and 40 IU vitamin E (vitamin A group) or 40 IU vitamin E (placebo group) were provided by Hoffman-La Roche, Basel, Switzerland. Only the manufacturer knew the contents of the capsules until after data collection and preliminary analysis of the results. After 22 months of storage, a sample of capsules of both colours was sent to the manufacturer for analysis; 15 % of the vitamin A activity had been lost. New capsules were obtained to complete the study. Each interviewer was assigned one of the colours for the duration of the study to minimise errors. Randomisation was done by household. To facilitate locating subjects in subsequent rounds, interviewers recorded identification data, addresses, and directions on colourcoded household cards that matched the colour of the trial capsule. Upon arrival at a village, the supervisor in consultation with village leaders chose a central location to carry out anthropometric measurements. Interviewers conducted a house-to-house survey beginning at the northeastern end of the village. Assignment to treatment group was achieved by the two interviewers visiting alternate households throughout the village. If the household did not include children between the ages of 9 and 72 months or the members refused to take part in the study, the interviewer went to the next household. Otherwise, the interviewer issued a unique identification number for each eligible child. ADDRESSES Harvard Institute for International Development, Cambridge (M. G Herrera, MD, P Nestel, PhD, L. Weld, PhD) and the Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (M. G. Herrera), Division of Nutrition, Ministry of Health, Khartoum, Sudan (A. El Amin, K. A. Mohamed, MD), and Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA (W. W. Fawzi, MD) Correspondence to Dr M G Herrera, Harvard Institute for International Development, 1 Eliot Street, Cambridge, MA 02138, USA.
268
Dietary, social, economic, and demographic data were recorded questionnaire. The birth date of each child was ascertained
on a
with the local Muslim calendar and the birth certificate if available. A 24 h dietary recall survey of foods containing vitamin A was done and the occurrence of diarrhoea (three or more loose or watery stools per 24 h), pyrexia, cough (present for at least 24 h), and measles during the preceding 7 days was also recorded. Mothers were carefully questioned about the presence of night blindness in the enrolled children. The interviewer, using a loupe (x 2 magnification), examined the children’s eyes for Bitot’s spots, corneal scars, and corneal ulcers. Interviewers emptied the contents of one study capsule (vitamin A or placebo) into the mouth of all non-xerophthalmic children. Mothers then took the children to the field site where they were weighed to the nearest 0.1 kg (Salter hanging scale). Height (or recumbent length for children under 85 cm) was measured to the nearest 0.1 cm with a locally made anthropometer. Questionnaires and household identification cards were checked daily by the supervisor for accuracy, consistency, and completion. The supervisor repeated the ocular examinations of all xerophthalmic subjects. If xerophthalmia was confirmed, 200 000 IU vitamin A with 40 IU vitamin E was given (also provided by Hoffman-La Roche), if the diagnosis was refuted, the child was given the appropriate study capsule. Xerophthalmic children were removed from the remainder of the study. All children were given a vitamin A capsule at the end of the study. Household surveys were repeated 6, 12, and 18 months after enrolment. At each follow-up, birth date, morbidity, dietary intake of vitamin A, and anthropometric measurements were recorded as well as symptoms associated with death when that was the outcome. Ocular examinations were repeated and study capsules were administered. Children with xerophthalmia were treated with vitamin A and not followed up further. Children who for any reason were not available were not given further trial capsules but their survival status was ascertained from family or neighbours. Supervisors attended 13% of all interviews. Senior project staff visited each team in the field once every 2 weeks to attend interviews, review questionnaires, monitor anthropometric measurements, and discuss problems. On alternate weeks the teams met with the project staff at headquarters.
Data processing and analyses Data recorded on questionnaires were entered on diskettes, and verbally cross-checked against the questionnaires. Verification programs were run after each round with the Centers for Disease Control Anthropometric Software and SPSS PC version to identify outliers and inconsistent answers; original forms were checked and transcription errors were corrected. Birth dates were converted from the Muslim to the western calendar by computer. The four dates provided by the mother were compared with the birth certificate, when available, and a final birth date was assigned when at least two of the available dates coincided within a month; a birth date could not be assigned to 12% of the children. The occurrence of diarrhoea, pyrexia, cough, and measles during the 7 days preceding each of the four surveys was used to calculate the morbidity burden by adding the number of symptoms during that time. To identify risk factors for mortality, morbidity data obtained at the initiation of each of the three periods of observation were used. Approximate vitamin A consumption was estimated from the 24 h dietary intake survey data with African and US Department of Agriculture food composition tables.1o,11 An average portion was assumed since the questionnaire established only whether or not a certain food item had been consumed during the day before the survey. The data reflect differences in consumption between subjects but should not be regarded as a precise measure of actual intake. Dietary data were collected every 6 months at the beginning of each round of observation. For analyses involving the first 6 months of observation, baseline dietary data were used; averages of baseline and round-2 data were used for analyses pertaining to the second period; averages of baseline, round-2, and round-3 data were used for analyses pertaining to the third period of observation.
printed,
Status of study cohort throughout study.
Non-compliant subjects are those who missed dose at 6 mo and/or those who missed dose at 12 mo. They had a lower mortality rate because they were at risk only during rounds 2 and 3, when overall mortality was lower.
Height-for-age and weight-for-height
Z
scores were
calculated
by reference to the National Center for Health Statistics (NCHS) standards.l2 Children who fell below - 2 Z score in height-for-age classified as stunted, those who fell below - 2 Z score in weight-for-height were classified as wasted. Sanitation was assessed only at baseline. The presence of water in the household proved to be a proxy for other sanitation-related variables such as the presence of a latrine in the home. Poverty was rated on a scale of one to four based on the quality of the dwelling and household possessions at the time of the initial survey. Treatment effects were calculated by use of relative risks (RR) with 95 % confidence intervals (CI). Mortality rates were calculated for children enrolled at baseline and alternatively for those who actually received a trial capsule in the previous round. Logistic regression and discrete time survival analyses13 were used to estimate the overall treatment effect adjusted for baseline differences and to identify predictors of mortality, including dietary vitamin A intake. Data analyses were done with SAS/PC v6.04.
were
Results There were 17 031 eligible households enrolled at baseline. 29 615 children were screened, of whom 862 (3%) were diagnosed as xerophthalmic, treated, and not followed up further (figure). Thus, 28 753 children were enrolled. 3320 children did not receive one or two of the three vitamin A or placebo capsules. Most of this non-compliant group consisted of children absent from the household at the time of follow-up, whereas others had moved away or refused to take part further. As a group, the non-compliant children tended to be from poorer households than those who continued in the study. However, there were no significant
269
TABLE I-BASELINE COMPARISONS OF NON-XEROPHTHALMIC CHILDREN
TABLE III-MORTALITY BY AGE, SEX, NUTRITIONAL STATUS, AND MORBIDITY
Data shown as placebo/vitamin A. *No deaths occurred in children 72 months.
in the placebo group (RR 1 06,95% CI 0’82-1’37) (table II). Controlling for region, study round, baseline anthropometry, baseline morbidity, sex, and all baseline differences between vitamin A and control groups did not change the results, nor did inclusion of the 8 deaths among non-compliant children. Vitamin A administration had no effect on mortality in either sex. Mortality was much higher among children under the age of 36 months, but there were no effects of supplementation on mortality within the 0-35 months, 36-71 months, and 72-and-over age-groups. Differences in mortality between vitamin A and control groups were not statistically significant within nutritional status subsets *Rated by enumerators on a scale of 1-3, tRated by enumerators on a scale of 1-4, based on characteristics of dwelling and household possessions tOwnershlp of bicycle or car. In the previous 7 days IlWasted < - 2 Z score weight/height; stunted < - 2 Z score height/age Unrts are retinol equivalents (SD)
differences between vitamin A and placebo groups in the number of non-compliant subjects or in their ages, sex, or nutritional status. At the end of the study, the survival status was known for all children originally enrolled apart from those excluded because of xerophthalmia and 167 others who could not be traced. The figure summarises the status of the cohort throughout the study.
Baseline characteristics Baseline characteristics of the sample by treatment group are shown in table I. There were no important differences between vitamin A and placebo groups in rate of xerophthalmia (2-8 vs 2-9%), vitamin A intake, age distribution, or nutritional status.
Effect of supplementation
on
mortality
During the 18 months of follow-up, there were 120 deaths
(8-4/1000) in the vitamin A group and 112 deaths (7-9/1000)
(table III). Exclusion of 24 deaths due to causes unlikely to be affected by vitamin A (motor vehicle accidents, scorpion bites, burns) did not change the above results. There were no significant differences between vitamin A and placebo groups in symptoms associated with death, although there were fewer deaths associated with shortness of breath in the vitamin A group (table IV). De-novo appearance of night blindness was reduced by about 50 % in the vitamin A group (0-53, 0,28-0,99) compared with the placebo group. Denovo incidence of Bitot’s spots was reduced by vitamin A supplements (0-89, 0°Trl °09). Dietary vitamin A irrespective of group was also associated with reduced incidence of night blindness (top quintile vs bottom quintile 0-54, 0-22-1-34) and Bitot’s spots (top quintile vs bottom
quintile 0-70, 0 51-0-96). Variables previously identified as important in bivariate analyses were included sequentially in a model designed to explain mortality. As expected, mortality was associated with age, nutritional status, morbidity, round, and region. Children who lived in the relatively privileged region 3 were more likely to survive; illness during the week before each TABLE IV-SYMPTOM-SPECIFIC MORTALITY BY TREATMENT
GROUP*
TABLE II-VITAMIN A SUPPLEMENTATION AND SURVIVAL
*Includes 140 children with xerophthalmia at round 4 tlncludes deaths among non-compliant children (3 vitamin A, 5 placebo)
*Symptoms reported by principal
supervisor-
270
TABLE V-MORTALITY RISK ASSOCIATED WITH VARIOUS FACTORS
Controlling for all other variables in the model. *Follow-up period 6-12 2 mo (round 2) tResidence
in EI Jaeli, region where mortality was lower tAge at beginning of each round (increments of 12 mo) §No of symptoms (diarrhoea, pyrexia, cough, measles) in week preceding each
round.
DWater supply in house Poverty= rating of household by enumerator DietvitA=dietary mtake of vitamin A (Increments of 100 retinol equivalent) Supplementation = administration of 200 000 IU vitamin A every 6 mo.
round of observation children with lower
associated with the risk of dying; weight-for-height or height-for-age were at a much higher risk of death than were normal children; and low dietary intake of vitamin A significantly increased risk of mortality even when the model included round, region, age, anthropometry, morbidity, poverty, sanitation, and treatment with vitamin A (table v). was
Discussion The results show that in Sudan, supplements of 200 000 IU vitamin A taken every 6 months had some protective effect on incidence of eye signs and symptoms of vitamin A deficiency but did not lower child mortality. The lack of effect on child mortality accords with the findings of the Andra Pradesh study where 200 000 IU vitamin A were also given every 6 months.7 By contrast, distribution of 200 000 IU vitamin A every 4 or 6 months in Nepal8 and Indonesia6 resulted in a 30-34% reduction in child mortality. Our findings also differed from those of the study in Tamil Nadu in southern India where the weekly distribution of 8333 IU vitamin A was associated with a 54% reduction in child
mortality.9 To understand these apparently conflicting outcomes, it is necessary to keep in mind the wide differences in the settings where the studies were conducted, the diversity of treatment protocols, and the lack of precise information about severity of vitamin A deficiency in the study populations. The administration of 200 000 IU vitamin A every 6 months may have been inadequate to redress severe depletion. Of the three studies that have used this treatment regimen, only the one in Indonesia’where the baseline prevalence of eye signs was the lowest, showed that vitamin A supplementation reduced mortality. In the Sudan study, the modest effect of supplementation in preventing de-novo appearance of eye signs of vitamin A deficiency supports the hypothesis that vitamin A every 6 months is inadequate. A smaller but more frequent intake of the vitamin in an adequate diet or by administration of weekly supplements, as in the Tamil Nadu trial or through food fortification/4 may be more effective than the administration of massive doses 6 months apart.15,16 In Tamil Nadu, children with xerophthalmia were treated with 200 000 IU vitamin A and then assigned randomly to either vitamin A or placebo groups: the weekly administration of the small dose of vitamin A proved effective in reducing mortality even
finding suggests that the 200 000 IU dose given as treatment was insufficient to protect children who did not receive the weekly supplement thereafter. Vitamin A supplementation may have failed to lower mortality because deficiency was not severe enough. Our study included households of differing socioeconomic status and vitamin A intake; there was, however, no indication that supplementation reduced mortality even among the lowest quintile of vitamin A intake or among the poorest households. Comparison of baseline rates of xerophthalmia across studies does not suggest that the severity of vitamin A deficiency influenced the efficacy of supplementation. Tamil Nadu had the highest rate followed by, in descending order, Hyderabad, Nepal, Sudan, and Indonesia. However, eye signs of vitamin A deficiency are an imprecise endpoint: they were used because other practical and more valid methods were not available. The effect of vitamin A supplementation may be especially effective among deficient subjects with lifethreatening infections. By, comparison across studies, mortality rates in the control groups were higher in the three sites where vitamin A supplements were effective than where vitamin A had no effect. This observation is compatible with a protective effect of vitamin A in life-threatening infections among deficient subjects.17 Vitamin A reduces case-fatality in severe measles2-4 and seems to lower mortality without altering the incidence of infectious disease.9,17 Diet and intestinal parasite infestation may have influenced the effect of vitamin A supplementation on mortality. Dietary fat affects absorption of vitamin A and thus may modify the effects of the vitamin on child survival. Other nutrient deficits (eg, zinc) may render subjects unresponsive to vitamin A supplementation;"I,19 such effects have not been assessed by any of the randomised trials to date. Further work is needed to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Factors such as frequency of supplementation, severity of vitamin A deficiency, incidence and severity of specific infectious diseases, and concurrent nutrient deficits need to be investigated. Also, the possiblity that vitamin A supplements are protective against certain pathogens but not against others deserves attention. We have also shown that various risk factors contributed independently to the risk of death. That mortality was lower during the second and even lower during the third 6-month period, irrespective of the capsule received, reflects both the ageing of the cohort and a reduction in the number of subjects at most risk, since they had died during preceding observation periods. Low dietary intake of vitamin A significantly increased the risk of mortality (controlling for morbidity, anthropometry, round, region, poverty, and sanitation), suggesting that ingestion of small but frequent amounts of vitamin A was more effective in reducing mortality than was administration of large doses of the vitamin at 6-monthly intervals. Such a conclusion is supported by the results of the Tamil Nadu study and those of a monosodium glutamate fortification programme in Indonesia.9,14 On the other hand, it is important to keep in mind that the association between dietary vitamin A and mortality in our study, though robust enough to persist after controlling for all the factors tested in table v could still be confounded by household characteristics that were not measured. among this subset of the cohort. This
271
In conclusion, large doses of vitamin A delivered every 6 months may not be sufficient to ameliorate deficiency in some settings, perhaps as a result of other dietary deficits. Conversely, the differences in outcomes between trials may be related to severity of deprivation and burden of disease: mortality rates were higher at the sites where vitamin A was effective. Further investigation of factors that modify the efficacy of vitamin A supplementation on mortality is needed to guide policy formulation. In accordance with findings in other developing countries, Sudanese children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. There were differences in mortality associated with dietary intake of vitamin A even after controlling for indicators of socioeconomic status and sanitary conditions of the home. A reduction in poverty, improvements in sanitation, and access to adequate diets should remain the goals of child survival efforts. Assuring adequate levels of intake of vitamin A by increasing dietary intake through fortification of staple foods or by providing small supplementary doses frequently may be more effective in some settings than distribution of massive doses of vitamin A. Improvement of vitamin A intake by whatever possible and effective means, including periodic distribution of large doses, continues to be of high priority in areas where the deficiency is prevalent and nutritional blindness a common and tragic occurrence.
Center for Health Statistics, November 1977. (DHEW
13.
14.
publication [PHS] 78-1650). Singer JD, Willett JB. Modeling the days of our lives: using survival analysis when designing and analyzing longitudinal studies of duration and the timing of events. Psychol Bull 1991; 110: 268-90. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988;
48: 1271-76. 15. Swaminathan MC, Susheela TP, Thimmayamma BVS. Field prophylactic trial with a single annual oral massive dose of vitamin A. Am J Clin Nutr 1970; 23: 119-22. 16. Gopalan C. Combating vitamin A deficiency-need for a revised strategy. In: Recent trends in nutrition. Proceedings of First International Symposium of the Nutrition Foundation of India. Oxford: Oxford University Press, 1991 (prefatory chapter). 17. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC. Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. Am J Clin Nutr 1991; 54: 568-77. 18. Glover J. Factors affecting vitamin A transport in animals and man. Proc Nutr Soc 1983; 42: 19-30. 19. Udomkesmalee E, Dhanamitta S, Sirisinha S, et al. Effect of vitamin A and zinc supplementation on the nutriture of children in Northeast Thailand. Am J Clin Nutr 1992; 56: 50-57.
SHORT REPORTS Simian immunodeficiency virus needlestick accident in a laboratory worker
We thank Dr Walter Willett and Dr John Orav for valuable advice throughout the study, Dr El Fatih El Samani for help in the planning and early phases of the project, the USAID mission in Khartoum for their invaluable support, the field staff whose hard work made the study possible, Dr Elizabeth Allred for her assistance in data management, Hoffinan-La Roche Task Force Sight and Life Program for provision of vitamin capsules and for conducting the assays, and Ms Jill Arnold for her assistance in the preparation of the manuscript.
This study was carried out under cooperative agreement No. DAN-0045G-SS-6067 of the Office of Nutrition, US Agency for International Development (USAID), Washington, DC, and the Harvard Institute for International Development, Cambridge, MA, USA, and the Division of Nutrition, Ministry of Health, Khartoum, Sudan.
REFERENCES 1. Sivakumar B, Reddy V. Absorption of labelled vitamin A in children during infection. Br J Nutr 1972; 27: 299-304. 2. Barclay AJG, Foster A, Sommer A. Vitamin A supplements and mortality related to measles: a randomized clinical trial. BMJ 1987;
294: 294-96. Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990; 323: 160-64. 4. Sommer A, Hussaini G, Tarwotjo I, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983; ii: 585-88. 5. Sommer A. Mortality associated with mild, untreated xerophthalmia. Trans Am Ophth Soc 1983; 81: 825-53. 6. Sommer A, Djunaedi E, Loeden AA, et al. Impact of vitamin A supplementation on childhood mortality. Lancet 1986; i: 1169-73. 7. Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990; 336: 1342-45. 8. West KP Jr, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; 338: 67-71. 9. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323: 929-35. 10. United States Department of Health, Education and Welfare, Public Health Service, and the Food Composition and Planning Branch of the Food and Agricultural Organization. Food composition tables for use in Africa. Rome: FAO, 1968. 11. United States Department of Agriculture, Agricultural Research Service. Composition of foods, Agriculture Handbook No. 8-1. Washington, 3.
Hussey GD,
DC, USDA, November, 1976. 12. Hamill PVV, Drizd TA, Johnson CL, et al. NCHS growth curves for children birth-18 years United States. Hyattsville, MD: National
The macaque monkey infected with simian immunodeficiency virus (SIV) is an animal model of the acquired immunodeficiency syndrome. We investigated a laboratory worker who was exposed by needlestick accident to blood from an SIVinfected macaque. Seroreactivity to SIV developed within 3 months of exposure, with antibody titres peaking from the third to the fifth month and declining thereafter. Polymerase chain reaction for SIV sequences and cultures of peripheral-blood mononuclear cells failed to show infection. Inoculation of an SIV-negative monkey with blood from the worker did not cause infection. Animal-care and laboratory workers should adhere strictly to recommended procedures to avoid accidental exposures when working with SIV-infected animals or
specimens.
virus (SIV) infection of valuable animal model for the study of the acquired immunodeficiency syndrome (AIDS).12 There is a potential risk that human beings working in research laboratories may be exposed to SIV.3 To date, however, no SIV infection in human beings has been reported. We Simian
immunodeficiency
macaques is
a
