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Indian J GastroenterolDOI 10.1007/s12664-011-0146-0 Effect of bovine colostrum-based food supplementin the treatment of HIV-associated diarrhea in NorthernUganda: a randomized controlled trial F. O. Kaducu & S. A. Okia & G. Upenytho & L. Elfstrand &C.-H. Florén Received: 23 November 2010 / Accepted: 10 November 2011 # Indian Society of Gastroenterology 2011 stool frequency was recorded, and body weight and body Aim HIV-associated diarrhea is common in HIV/AIDS mass index were evaluated at weeks 1, 4 and 9. Baseline CD4 patients in developing countries. An earlier uncontrolled study + count was measured at baseline and at week 9.
showed that a nutritional product made from bovine colostrum Results Mean daily stool frequency decreased by 79% from (ColoPlus®) alleviates HIV-associated diarrhea. We performed 7.5 to 1.3 motions over the study period in patients on a randomized single-blind controlled trial of addition of colostrum-based supplement, compared to a 58% reduction colostrum-based supplement (ColoPlus®) to standard anti- in controls (p<0.001). Self-reported fatigue was reduced by diarrhea treatment in HIV/AIDS patients with diarrhea.
85% in patients on colostrum-based supplement by week 9 Methods Eighty-seven adult patients with HIV-associated compared to 43% reduction amongst controls (p<0.001).
diarrhea were recruited at Gulu Hospital and four community Patients on colostrum-based supplement had 11% increase clinics in Northern Uganda. Forty-five patients were random- (p<0,001) in mean body weight and body mass index by ized to receive 50 g of colostrum-based supplement twice a week 9, but no changes were observed in control subjects.
day for 4 weeks in addition to standard anti-diarrhea Mean CD4+ count increased by 14% for patients on treatment, and 42 patients received standard anti-diarrhea colostrum-based supplement, in contrast to 12% decrease treatment alone. Patients were followed up for 9 weeks. Daily in controls (p<0.001).
Conclusions This study shows that addition of colostrum-based supplement to standard therapy is effective in treatment of HIV-associated diarrhea.
Department of Public Health,Gulu University Faculty of Medicine,Gulu, Uganda Keywords CD4+. Colostrum. Colostrum-supplementation. Diarrhea. HIV. HIV-associated diarrhea S. A. OkiaGulu Independent Hospital and Gulu Women EconomicDevelopment and Globalisation,Gulu, Uganda Uganda is located in East Africa and has a population of Community Health Department, Gulu Regional Referral Hospital,Gulu, Uganda about 30 million, of which nearly 980,000 are people livingwith human immunodeficiency virus (HIV). Gulu in northern Uganda is one of the districts hardest hit by Department of Clinical Sciences, Skåne University Hospital, acquired immunodeficiency syndrome (AIDS). Data from HIV sentinel surveillance site at Lacor Hospital reveal that Gulu district has HIV prevalence rate of 11.9% [].
Department of Clinical Sciences/Medicine, The Uganda Ministry of Health Policy on HIV/AIDS Skåne University Hospital, Lund University, care ranks nutritional intervention as a key component of SE 23940 Lund, Swedene-mail: claes-henrik.floren@med.lu.se the comprehensive care package for HIV/AIDS patients HIV-infected patients are commonly faced with malnutri- commercially produced nutritional supplements (immune tion and chronic diarrhea, requiring prolonged or recurrent boosters) during the previous 48 h; those with known antibiotic treatment. Studies have shown that in 30% of allergy or intolerance to milk and milk-products, and patients with HIV-associated diarrhea, enteric pathogens cannot be identified; and of the remaining 70%, only abouthalf of the identifiable etiological agents were treatable with antibiotics []. This means that only about 35% of patientswith HIV-associated diarrhea improve on regular treatment The study was an open-labeled, randomized, clinical trial.
One group of patients received 50 g of colostrum-based The above problems faced by HIV-infected patients with supplement twice a day for 28 days, in addition to the chronic diarrhea could be addressed by the use of bovine "regular care" currently offered to patients with diarrhea in colostrum products. Colostrum contains high titers of Uganda. The second group, serving as the control group, antibodies or immunoglobulin active against a wide range received only the "regular care" for HIV patients with of bacterial, viral and protozoa pathogens as well as against diarrhea until the diarrhea subsided. Randomization was done using a table of random numbers, and a unique ColoPlus® is bovine colostrum-based food product in number was allocated to each study subject. These random porridge form, is administered orally, with no known side numbers were matched to the study identification numbers effects reported so far. An earlier open-labeled observa- and were used to allocate either treatment protocol.
tional study from Nigeria indicated clinical improvement of "Regular care" of HIV-associated diarrhea currently patients with HIV-associated diarrhea on regular supple- involves fluid and electrolyte replacement, use of anti- diarrheal drugs and antibiotics in appropriate doses as well We evaluated the effects of a colostrum-based supple- as good nutrition using locally available food items.
ment (ColoPlus®), using a randomized single-blind trial, on Patients were followed up at weekly intervals in the clinics diarrheal frequency, immunological response and nutritional status of patients with HIV-associated diarrhea.
It was assumed that the proportion of patients with HIV-associated chronic diarrhea whose diarrhea would subside after regular treatment, including antibiotics was 35% []. Itwas further assumed that the proportion of patients with The study was done between October 2007 and June 2008 HIV-associated diarrhea whose diarrhea would subside after in Gulu Regional Referral Hospital HIV/AIDS Clinic and receiving colostrum-based supplement was 72% four community outreach sites (mobile clinics) located in Assuming 20% loss to follow up of the calculated sample four internally displaced persons' (IDP) camps in Gulu and size (6.4≈7 patients), the minimum sample size for each Amuru districts of northern Uganda. Laboratory tests were arm was 39≈40. For both arms, a minimum of number of performed at the Joint Clinical Research Center (JCRC) specialized laboratory in Gulu. Samples collected from Patients who met the selection criteria were randomly patients at the community outreach sites were transported assigned to either of the treatment groups. The purpose of under optimal conditions to the JCRC laboratory within 4 h the study was explained to them by a study nurse and informed consent was taken prior to enrolment. A total of45 patients were recruited on the colostrum-based supplement (intervention) arm and 42 were recruited on the control arm(Fig. ).
Study patients were recruited, examined and followed up at At the time of enrolment, baseline socio-demographic both the hospital HIV/AIDS clinic and the community data and clinical information were recorded on a pre-coded, outreach sites. The inclusion criteria were HIV-positive pre-tested standardized questionnaire. A clinic staff admin- patients aged 18 years or more; diarrhea with stool istered the questionnaire, designed in English and translated frequency of four or more motions per 24 h for more than into the local language (Luo), to obtain and record the 7 days; patients not receiving anti-retroviral (ARV) therapy; socio-demographic information, and baseline symptoms and those who gave their informed consent. Patients with and examination findings. Other important baseline param- stool frequency of less than 4 motions per 24 h or those eters documented included self-reported frequency of stool with diarrhea lasting 7 days or less; those who had used per 24 h, and self-estimated fatigue level, body weight, CD4+ counts and were startedon ARVs within 1 week, 1 usedantibiotics in previous 48 h, 3declined to consent) body mass index, stool microscopy results, hemoglobin up visits. For those who could not read and write, the study level, serum albumin, and CD4+ counts.
nurse filled in the dairy card using patient recall. Fatigue During weeks 1 to 4, patients in the intervention arm level was estimated by the patient using a visual analogue received 50 g of colostrum-based supplement twice daily.
scale (VAS) consisting of a line drawn with equal interval They also received regular care until the diarrhea ceased.
scale from 0 to 10, where 0 represented no fatigue and 10 Compliance to colostrum-based supplement intake was represents the worst fatigue level possible. Body weight checked at weekly intervals and was over 95%. Patients and height were measured by the clinic nurse, and the body in the control arm received only the regular care until mass index (BMI) was calculated from these values. Stool microscopy, serum albumin and hemoglobin measurements The main outcome measures, which included stool were done at the JCRC laboratory using standard procedures.
frequency per 24 h, fatigue level, body weight, body mass CD4+ count was determined using flowcytometry.
index, stool microscopy, hemoglobin and serum albumin,were assessed at weeks 4 and 9 in all patients. CD4+ count was repeated at week 9. Measurements at 9 weeks wereused to examine whether colostrum-based supplement had Data were entered in EPI Info, exported to and analyzed a protracted effect on the outcome measures 5 weeks after using the Statistical Package for Social Sciences computer software (SPSS version 10.0). Categorical outcomes were Stool frequency was recorded by the patient on a dairy analyzed using chi-squared test, and continuous variables card on a 24 hourly basis throughout the study period. The were analyzed using independent sample t-test and analysis records for each patient were regularly verified for of variance. Multiple logistic regressions method was used completeness by the clinic staff during the weekly follow- ColoPlus usage was accepted by the Ethical Committee of The mean 24 h frequency of stool at time of enrolment Lund University, Sweden in September 2002 (LU-472-02) into the study was 7.2 motions per day, while the which approved of the use of ColoPlus on adult patients average duration of diarrhea was 16.6 days. Patients on with HIV-associated diarrhea. Ethical approval for the the two treatment groups were similar in these baseline Uganda study was obtained from Gulu University Faculty parameters. Overall, 36.8% of the patients had fever at of Medicine Institutional Research Committee (IRC) and baseline. The mean duration of fever at enrolment was the Uganda National Council for Science and Technology similar in both treatment groups, 8.7 days and 7.2 days for colostrum-based supplement and control groups, ColoPlus is patented by ColoPlus AB, Malmö, Sweden respectively. Seven patients had history of other chronic and is manufactured in accordance with the Swedish illnesses in the previous 1 month: 5 patients were National Board of Food Administration. ColoPlus is in treated for tuberculosis and 2 for peptic ulcer disease.
dry-powder form with particles 0.3-7.0 mm in diameter.
The majority of the patients (93%) were on septrin The particle size allows slower intestinal transit than that prophylaxis, with mean duration of septrin use being for milk. The active part of the product is collected and 13.8 months. Seventeen (20%) patients were using other processed from bovine colostrum in such a way that its antibiotics at the time of enrolment; antibiotics used by antimicrobial properties are preserved. The active part then patients in the previous 1 month included: amoxicillin, is added to a vehicle of dry rice flakes, and banana flakes ciprofloxacin, ampicillin, doxycycline, chloramphenicol and and sugar are added to give a pleasant taste. The particles metronidazole (Table ). Patients on colostrum-based sup- swell after mixing with water, and the starch-containing plement did not differ from the controls in septrin and other vehicle has a protective role for the active substances in the antibiotics use. None of the patients was on any nutritional bowel and contributes to increasing the transition time ColoPlus is packed in portions of 50 g to be taken twice a day, with the first and last meal of the day, giving aninterval of about 12 h. Each portion is mixed by the patient Patients on both treatment groups did not differ in their with 120 mL of boiled lukewarm water (max 60°C) to mean baseline hematocrit, hemoglobin, and white blood porridge-like consistency just before ingestion. Each por- cell counts. However, patients on colostrum-based supplement tion of the product contains 3-4 g of immunoglobulin, the had relatively lower mean CD4+ counts and mean serum main part of which is constituted by IgG1. Growth factors, albumin compared to the control group.
such as IGF-1, TGF-β2, are positively correlated with Seven (8%) patients had identifiable micro-organisms immunoglobulin content of bovine colostrum ].
on stool microscopy; Trichomonas hominis was seen in The composition of ColoPlus product is as follows: 32% three patients, Giardia lamblia in two patients, and colostrum powder; 30% rice flakes; 14% banana flakes; Entamoeba histolytica and Hymelnolepsis nana in one 20% maltodextrin; and 4% sugar. Energy value of one sachet of ColoPlus, which equals 50 g, is 825 kJ, which isequivalent to 175 kcal.
The mean (SD) number of stool motions per day decreased from 7.5 (2.9) at enrolment to 1.6 (0.7) at week 4 in thecolostrum-based supplement group, and from 6.9 (3.2) to 2.9 (1.8) in the control group (p<0.001). The protractedeffect was seen after 5 weeks of stopping colostrum-based The mean age of all study participants was 36.7 years.
supplement. At 9 weeks, mean number of stool motions Participants who received colostrum-based supplement was 1.3 (1.6) in the colostrum-based supplement group, were younger than the controls; 34.5 years vs. 39.1 years compared to 2.7 (SD 3.5) in the control group (p=0.041) (p=0.018). Most of the study participants (n=60 [69%]) were females. The sex distribution, and socioeconomic Diarrhea, defined as stool frequency of more than 3 characteristics measured by education level and occupa- motions per day, on average ceased by day 7 for tion, were similar for the two groups. Twenty percent of patients receiving colostrum-based supplement and stool the participants did not have any formal education frequency was normal at week 9, 5 weeks after stopping colostrum-based supplement. The control subjects Table 1 Baseline demographic and laboratory characteristics of study participants by study group, n=87 achieved normalization of stool frequency at mean Patients who received colostrum-based supplement Previous studies that examined the effects of bovine reported greater improvement in their life and feeling of colostrum preparations, including one study with ColoPlus, wellbeing, with less fatigue as compared to the control in the treatment of patients with HIV/AIDS-associated group (Table ). There was 11.4% increase in mean weight diarrhea, have all been observational studies , , and mean BMI at week 9 among patients on colostrum- This is the first randomized single-blinded controlled based supplement (p<0.001) but there was no change in clinical trial using a colostrum preparation in the manage- weight in the control group (p=0.251). The serum albumin ment of HIV/AIDS patients presenting with chronic and hemoglobin was similar in both treatment groups at diarrhea. Our results indicate that colostrum-based supple- ment is effective in reducing the frequency of stool motionsand self-estimated fatigue levels, thereby improving a sense of patient well-being and functionality. The interventiongroup, who in addition to regular therapy received The mean CD4+ count increased by 14% at week 9 in the colostrum-based supplement, achieved weight gain and colostrum-based supplement group but was reduced by 12% had increased CD4+ cell counts. These findings are over the same follow up period among the controls (p<0.001) consistent with those seen in the previous observational study using colostrum-based supplement [].
Table 2 Effect ofcolostrum-based supplement on Table 3 Effects of colostrum-based supplement on self-reported fatigue and weight VAS Visual analogue scaleData are as mean (SD) Except for mean age at enrolment, mean CD4+ cell contrast, the count reduced by 12.2% in the control arm count and mean serum albumin levels, study patients in the over the 9 week study period. The observational study done two treatment arms were similar in all the other baseline in Nigeria documented an increase in the mean CD4+ socio-demographic characteristics, symptoms, signs and count of 125% after 4 weeks of ColoPlus treatment.
laboratory findings. The remarkable reduction in the mean Weight and body mass index improved in patients in the frequency of stool of 79% among patients on colostrum- intervention group; these findings are consistent with those based supplementation at week 4 in this randomized in the earlier study. However, no changes in hemoglobin controlled study is comparable to findings in the earlier and serum albumin were found in our study. These indices observational non-randomized study conducted in Nigeria probably need more time after recovery from diarrhea to The percentage reduction in the stool frequency among control patients was lower than that in the intervention There are certain limitations to this study. First it was group. The prolonged effect of colostrum-based supplement carried out as a single-blind randomized study without an on diarrhea was seen at week 9. The reason for this isocaloric placebo arm. We do, however, feel that an addition of a mere 350 kcal (which equals the caloric Micro-organisms could be identified in only a few stool contents in 100 g of colostrum-based supplement) to the samples and these were opportunistic infections. We cannot control group would not jeopardize our major conclusions.
rule out missed diagnosis on microscopy since we did not Also, we did not include an arm with antiretroviral therapy do stool cultures. However, previous studies have not as colostrum-based supplement should act as an adjunct to identified infective etiological agents in most HIV patients antiretroviral therapy, not a substitution for antiretroviral with diarrhea. Besides opportunistic bacterial infections, therapy. Also, in Northern Uganda antiretroviral therapy viral infections and HIV enteropathy are major causes of was not readily available at the time of the study.
This study thus provides evidence that bovine colostrum, Patients on colostrum-based supplement had a lower administered as ColoPlus, is effective in treating HIV- mean baseline CD4+ counts at enrolment. A selection bias associated diarrhea; it also reduces fatigue levels. Patients in the allocation of study participants to the treatment treated with bovine colostrum achieve greater weight gain, groups during randomization process cannot be ruled out.
increase in body mass index and show a good immunological However, in patients who received colostrum-based sup- response as demonstrated by a rise in CD4+ count. These plement, the mean CD4+ count increased by 14%; in effects can last for over 1 month after treatment is stopped.
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