The immunomodulatory nutritional intervention NR100157 reduced CD4+ T-cell decline and immune activation: a 1-year multicenter randomized controlled double-blind trial in HIV-infected persons not receiving antiretroviral therapy (The BITE Study).

BACKGROUND: The immunomodulatory nutritional product NR100157 was developed for human immunodeficiency virus (HIV)-infected individuals. We hypothesized that targeting the compromised gastrointestinal tract of HIV-infected individuals would result in systemic immunological benefits. METHODS: In a multicenter, randomized, controlled, double-blind trial, 340 HIV-1-positive adults not on antiretroviral therapy, with CD4(+) T-cell counts <800/µL, were given either NR100157 or an isocaloric and isonitrogenous control for 52 weeks. Primary outcome was CD4(+) T-cell count. Secondary outcomes included plasma viral load (pVL), safety, and tolerability. In a pilot study (n = 20), levels of CD4(+)CD25(+) and CD8(+)CD38(+) activation were measured (n = 20). The trial is registered at the Dutch Trial Register (NTR886) and ISRCTN81868024. RESULTS: At 52 weeks, CD4(+) T-cell decline showed a 40-cell/µL difference (P = .03) in the intention-to-treat population in favor of the immunomodulatory NR100157 (control vs active, -68 ± 15 vs -28 ± 16 cells/µL/year). The change in pVL from baseline was similar between groups (P = .81). In the pilot study, the percentage of CD4(+)CD25(+) was lower in the active group (P < .05) and correlated with changes in CD4(+) T-cell count (r = -0.55, P < .05). The percentage of CD8(+)CD38(+) levels was unaffected. CONCLUSIONS: The specific immunonutritional product NR100157 significantly reduces CD4(+) decline in HIV-1-infected individuals, and this is associated with decreased levels of CD4(+)CD25(+). (This nutritional intervention is likely to affect local gut integrity and gut-associated lymphoid tissue homeostasis, which in turn translates positively to systemic effects.) Clinical Trials Registration. ISRCTN81868024.

Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure.

Some individuals remain uninfected with human immunodeficiency virus type-1 (HIV-1) despite multiple high-risk sexual exposures. We studied a cohort of 25 subjects with histories of multiple high-risk sexual exposures to HIV-1 and found that their CD8+ lymphocytes had greater anti-HIV-1 activity than did CD8+ lymphocytes from nonexposed controls. Further studies indicated that their purified CD4+ lymphocytes were less susceptible to infection with multiple primary isolates of HIV-1 than were CD4+ lymphocytes from the nonexposed controls. This relative resistance to HIV-1 infection did not extend to T-cell line-adapted strains, was restricted by the envelope glycoprotein, was not explained by the cell surface density of CD4 molecules, but was associated with the activity of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. This relative resistance of CD4+ lymphocytes may contribute to protection from HIV-1 in multiply exposed persons.

Body mass repletion during ganciclovir treatment of cytomegalovirus infections in patients with acquired immunodeficiency syndrome.

Disseminated cytomegalovirus (CMV) infection is a common complication of acquired immunodeficiency syndrome and contributes significantly to its morbidity and mortality. Ganciclovir, a guanosine analogue, inhibits CMV replication in vitro and in vivo, and its use can stabilize the clinical course of an affected patient. We examined the changes in body composition that occurred in four untreated patients and in eight patients who were treated with ganciclovir for serious CMV infections. Untreated patients lost weight, depleted body cell mass, as determined from total-body potassium measurements in a whole-body counter, lost body fat, as estimated from anthropometric measurements, and had a progressive fall in serum albumin concentration. In contrast, treated patients gained weight, repleted body cell mass and body fat, and increased serum albumin concentration during a three-month follow-up. In this study, it was estimated that ganciclovir therapy resulted in a net energy conservation of 2629 kJ/d. The ability to promote body cell mass repletion may be considered a demonstration of the efficacy of ganciclovir in the treatment of serious CMV infections in patients with acquired immunodeficiency syndrome.

Localization of infection by the microsporidian Enterocytozoon bieneusi in the gastrointestinal tract of AIDS patients with diarrhea.

OBJECTIVE: We compared the level of Enterocytozoon bieneusi infection at different sites within the small intestine among patients with AIDS. DESIGN: The level of E. bieneusi infection of each patient biopsy was determined and compared using semi-thin plastic section light microscopy and transmission electron microscopy (TEM). PATIENTS, PARTICIPANTS: Nine subjects with chronic diarrhea who had endoscopic biopsies of either proximal (bulb) or distal (fourth portion) duodenum plus proximal jejunum (just past ligament of Treitz), either simultaneously or within a few months of each other were studied. All patients had TEM-confirmed diagnoses of E. bieneusi intestinal microsporidiosis. RESULTS: The intensity of infection was always greater in biopsies taken from the patients' jejunum compared with those taken from the duodenal bulb. In one patient, the duodenal bulb biopsy was negative while the jejunal biopsy, taken at the same time, was positive. The distal duodenum was usually, but not always, equal to the jejunum in terms of parasite burden. Esophageal, gastric, and colorectal biopsies from these and other patients were negative for E. bieneusi. CONCLUSIONS: For the diagnosis of E. bieneusi to evaluate chronic diarrhea in AIDS patients, upper intestinal endoscopy biopsies should be taken at the most distal site possible.

Systemic dissemination by a newly recognized intestinal microsporidia species in AIDS.

OBJECTIVE: Primarily to determine whether an intestinal microsporidian recently identified in AIDS patients disseminates from the bowel to infect other organs. DESIGN: Disseminated microsporidiosis has been reported in immunocompromised humans, but never due to Enterocytozoon bieneusi, the most common species in AIDS patients and one that evidently infects only enterocytes. In animals, dissemination follows ingestion of Encephalitozoon cuniculi spores, apparently via macrophages, and pathology occurs in, for example, kidneys and brain. A second, un-named Encephalitozoon-like intestinal microsporidia has been identified in five AIDS patients with chronic diarrhea; because it infects lamina propria macrophages, it was logical to investigate its dissemination. METHODS: Light and transmission electron microscopy were used to study urine sediment from four out of five patients with biopsy-documented small intestinal infection due to the second intestinal microsporidian. The gall bladder from one patient and autopsy specimens from an E. bieneusi-infected patient were similarly studied. RESULTS: Systemic dissemination was documented by detecting abundant spores, both free and within renal tubular and transitional cells, in the urine of two patients. Many of the lamina propria macrophages in these two patients' intestinal biopsies contained microsporidia, while those of the two negative patients either contained only Mycobacterium avium complex or only occasional parasites. The gall bladder was co-infected with this microspordian and with cytomegalovirus. At autopsy, the patient with documented enteritis due to E. bieneusi 2 years before death had disseminated microsporidiosis, not of E. bieneusi, but apparently of the second intestinal species. The microsporidian had caused severe tubulointerstitial nephritis. Parasites were also observed in non-parenchymal cells of the liver and bronchial epithelium. CONCLUSION: A newly described Encephalitozoon-like intestinal microsporidian, which causes chronic diarrhea in AIDS patients, can disseminate and cause renal pathology.

Effects of whey protein and resistance exercise on body cell mass, muscle strength, and quality of life in women with HIV.

OBJECTIVE: To determine the effects of whey protein, resistance exercise, and combined protein and exercise treatment on body cell mass (BCM), muscle strength, and quality of life (QOL) in HIV-infected women with reduced BCM. DESIGN AND SETTING: Prospective, randomized, controlled trial at a university hospital in New York City. METHODS: A volunteer sample of 30 HIV-infected women were randomized to whey protein (PRO), progressive resistance exercise (PRE), or combined treatment (PRO-PRE) for 14 weeks after a 6-week control period. The main outcome measures were body weight, BCM, skeletal muscle, fat mass, muscle strength, and QOL. RESULTS: There were no significant changes in BCM, strength, or QOL during the control period. PRO patients gained 3.6 kg (P = 0.001), and 2.5 kg fat (P = 0.002) with no change in BCM (0.5 kg; P = 0.07) or skeletal muscle (0.6 kg; P = 0.12). The PRE group increased BCM (0.74 kg;P = 0.03) and skeletal muscle (1.2 kg; P < 0.001) and decreased fat (1.7 kg; P = 0.02). PRO-PRE increased BCM (0.61 kg; P = 0.01) without change in skeletal muscle (0.6 kg; P = 0.30). Strength increased for both exercise groups (range, 40.6-95.3%; P < 0.001). The QOL physical activity score improved for PRE (P = 0.02) and worsened for PRO (P = 0.01). CONCLUSIONS: Resistance exercise significantly increased BCM, muscle mass, muscle strength, and QOL in HIV-infected women with reduced BCM. Whey protein had little effect on BCM accrual. Combined protein and exercise did not increase BCM in excess of gains achieved by exercise alone.

Effect of combination antiretroviral therapy upon rectal mucosal HIV RNA burden and mononuclear cell apoptosis.

BACKGROUND: Pathogen-negative diarrhea is common in HIV infection and has been associated with clinical symptoms, histopathology, HIV expression, CD4+ lymphocyte depletion, cytokine mRNA expression, and apoptosis of lamina propria mononuclear cells. OBJECTIVES AND METHODS: To examine the short-term (7-day) effects of treatment with combination antiretroviral therapies upon gastrointestinal symptoms and rectal mucosa in 15 HIV-infected subjects. RESULTS: Treatment was associated with significant decreases in the perception of abdominal bloating and cramps. Similar declines in RNA burden and rises in CD4+ lymphocyte counts were found in blood and mucosa. Treatment was also associated with a fall in the number of lamina propria mononuclear cells undergoing apoptosis by in situ labeling, a change that correlated with the change in mucosal viral burden. CONCLUSIONS: Peripheral blood and mucosal compartments are equally responsive to effective antiretroviral therapies. The detection of significant changes within 7 days of starting antiviral therapy implies that intestinal dysfunction may be a direct result of local HIV infection.

Refeeding after a fast in rats: effects on small intestinal enzymes.

The effect of resuming food intake after a period of starvation (refeeding) on the specific activities of selected rat intestinal enzymes was determined. The rate of weight gain was higher in refed animals than in control animals, without a difference in food intake. Fasting caused intestinal atrophy which reversed rapidly on refeeding. Fasting decreased the specific activities of sucrase, maltase, and galactokinase, but did not affect the specific activities of hexokinase, pyruvate kinase, or crypt thymidine kinase. Sucrase, maltase, hexokinase, pyruvate kinase, and thymidine kinase specific activities all rose above control values during refeeding. The overshoot in intestinal enzyme specific activities may help promote the rapid weight gain observed in refed rats and is an integral part of the total adaptation to fasting and refeeding.

Body composition studies in patients with the acquired immunodeficiency syndrome.

Body composition studies were performed in 33 patients suffering from the acquired immunodeficiency syndrome (AIDS). Studies included measurements of total body potassium, fat, and total body and extracellular water volumes plus serum retinol binding protein concentration, iron binding capacity, and albumin concentration. AIDS patients were underweight (p less than 0.001) and were depleted of potassium (p less than 0.001) with the lowest values occurring in patients close to death at the time of study. Body fat contents also were reduced. Intracellular water volumes were decreased in the AIDS patients (p less than 0.001) with a relative increase in extracellular water volume (p less than 0.001). Serum protein concentrations were decreased in the AIDS patients. Longitudinal studies did not demonstrate tissue repletion in patients with AIDS, despite apparent clinical stability. These studies demonstrate that severe, progressive malnutrition occurs in patients with AIDS. If malnutrition can be shown to have a deleterious effect upon the disease course, therapy of malnutrition may play an important role in the treatment of this disorder.

Prediction of body cell mass, fat-free mass, and total body water with bioelectrical impedance analysis: effects of race, sex, and disease.

The inability to precisely estimate body composition with simple, inexpensive, and easily applied techniques is an impediment to clinical investigations in nutrition. In this study, predictive equations for body cell mass (BCM), fat-free mass (FFM), and total body water (TBW) were derived from direct measurements through use of single-frequency bioelectrical impedance analysis (BIA) in 332 subjects, including white, black, and Hispanic men and women, who were both healthy control subjects and patients infected with the human immunodeficiency virus (HIV). Preliminary studies showed more accurate predictions of BCM when parallel-transformed values of reactance were used rather than the values reported by the bioelectrical impedance analyzer. Modeling equations derived after logarithmic transformation of height, reactance, and impedance were more accurate predictors than equations using height2/resistance, and the use of sex-specific equations further improved accuracy. The effect of adding weight to the modeling equation was less important than the BIA measurements. The resulting equations were validated internally, and race and disease (HIV infection) were shown not to affect the predictions. The equation for FFM was validated externally against results derived from hydrodensitometry in 440 healthy individuals; the SEE was < 5%. These results indicate that body composition can be estimated with simple and easily applied techniques, and that the estimates are sufficiently precise for use in clinical investigation and practice.

Modification of weight gain by an alpha-glucosidase inhibitor during refeeding in rats.

In rats, the period of refeeding after a fast is associated with accelerated weight gain without a concomitant increase in food intake. In this study the alpha-glucosidase inhibitor, acarbose, was used to delay carbohydrate absorption in normal adult rats, and the effects on body weight, food intake, and intestinal enzyme activities were determined. Refeeding with acarbose in the food (500 mg/kg) reduced the rate of weight gain compared to refeeding without acarbose but did not change food intake. Acarbose also lowered midjejunal mass and blunted the refeeding-induced rise in certain brush border disaccharidase and intracellular glycolytic enzymes. However, acarbose refed rats still had accelerated weight gain compared to nonfasted rats, implying that the refeeding response was not totally abolished. These studies suggest that inhibition of carbohydrate absorption during refeeding might have a role in the maintenance of diet-induced weight loss.

Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.

The impact of malnutrition on survival in AIDS was evaluated by examining the magnitude of body-cell-mass depletion as a function of time from death. Body cell mass was estimated as total body-potassium content and determined by whole-body counting. There was progressive depletion of body cell mass as patients neared death. The extrapolated and observed values for body cell mass at death were 54% of normal. Body weight had a similar relationship to death, with a projected body weight at death of 66% of ideal. We conclude that death from wasting in AIDS is related to the magnitude of tissue depletion and is independent of the underlying cause of wasting. The degree of wasting seen in this study is similar to historical reports of semistarvation, with or without associated infections. This observation suggests that successful attempts to maintain body mass could prolong survival in patients with AIDS.

Preservation of short-term energy balance in clinically stable patients with AIDS.

Malnutrition in patients with acquired immune deficiency syndrome (AIDS) is common and multifactorial. The possible causes of malnutrition were evaluated by performing studies of energy balance in five clinically stable outpatients with AIDS, six seronegative homosexual control subjects, and five seronegative heterosexual control subjects. The AIDS group was significantly depleted of body cell mass compared with the control subjects but the values did not change significantly over 6 wk. Food intake was normal in the AIDS group whereas intestinal absorptions of the pentose sugar xylose and of the triglyceride triolein were both significantly diminished. The AIDS patients were hypometabolic as compared with the control subjects and with predictions of metabolic rate based on the Harris-Benedict equation. We conclude that short-term energy balance can be maintained in clinically stable patients with AIDS. Hypometabolism is an appropriate metabolic response to the combination of body-cell-mass depletion and nutrient malabsorption.

Enteral alimentation and repletion of body cell mass in malnourished patients with acquired immunodeficiency syndrome.

The aim of this study was to determine the feasibility, tolerance, and efficacy of enteral feeding in malnourished AIDS patients. This was a prospective study of eight AIDS patients with severe eating disorders associated with systemic diseases. A defined diet was administered through an endoscopically placed gastrostomy tube. Body composition studies and selected serum and immunologic studies were done at baseline and monthly for 2 mo. Enteral feeding was associated with an increase of approximately 14% in total body potassium, an index of body cell mass (P less than 0.02), and an increase in body fat content (P less than 0.002). Serum albumin concentration (P less than 0.005) and iron-binding capacity also rose. Serum immunoglobulins did not change. The numbers of total lymphocytes (P less than 0.005) and CD8+ cells rose but CD4+ cells did not change. The tube and enteral feedings were well tolerated. These results demonstrate that enteral feeding may result in body-cell-mass repletion in malnourished AIDS patients.

Body-fat measurement in patients with acquired immunodeficiency syndrome: which method should be used?

Malnutrition is common in patients with acquired immunodeficiency syndrome (AIDS), which distorts the chemical contents in the fat-free mass (FFM) and alters the assumptions underlying the traditional methods for calculating body-fat content so that such measurements may not be accurate. In vivo neutron-activation analysis (IVNA) measures FFM independently of the traditional assumptions, thereby providing more accurate measurements of body fat. We compared seven methods for measuring body fat in 18 male patients with AIDS: IVNA, total body water (TBW by 3H2O dilution), total body potassium (TBK by 40K counting), dual-photon absorptiometry (DPA), bioelectrical impedance analysis (BIA), and two well-calibrated anthropometric methods. FatTBW and fatDPA were not significantly different from fatIVNA. FatTBW gave the highest correlation with fatIVNA and the smallest SEE of +/- 1.8% (1.1 kg). The traditional and widely available TBW and the newer DPA method provide reliable estimates of fatIVNA in patients with AIDS.

Fat distribution in HIV-infected patients reporting truncal enlargement quantified by whole-body magnetic resonance imaging.

BACKGROUND: Antiretroviral therapy has improved the prospects for people infected with HIV, but some develop a syndrome of profound body habitus and metabolic alterations that include truncal enlargement. OBJECTIVE: The purpose of this study was to define the body-composition changes associated with this syndrome by using techniques with the power to estimate regional body composition. DESIGN: We compared whole-body and regional skeletal muscle and adipose tissue contents measured by magnetic resonance imaging and dual-energy X-ray absorptiometry (DXA) in 26 HIV-infected patients and 26 matched control subjects. Twelve of the HIV-infected patients had evidence of truncal enlargement. RESULTS: HIV-infected men and women who noted truncal enlargement had similar amounts of skeletal muscle and subcutaneous adipose tissue but greater visceral adipose tissue than HIV-infected patients without truncal enlargement; these values were larger in men (P < 0.001) than in women (P = 0.08). The ratio of visceral to subcutaneous adipose tissue was greater in both men (P < 0.02) and women (P = 0.05) with truncal enlargement. Two subjects with MRI-confirmed visceral adiposity syndrome (VAS) were not taking protease inhibitors. CD4+ lymphocyte counts were higher (P < 0.001) and plasma viral burdens tended to be lower (P = 0.08) in HIV-infected patients with VAS. CONCLUSIONS: There was significantly more visceral adipose tissue in the subgroup of HIV-infected patients with truncal enlargement than in those without this sign. VAS occurs in both men and women, is associated with higher CD4+ lymphocyte counts and lower plasma HIV viral burdens, and is not limited to those receiving protease inhibitor therapy.

Relative influences of sex, race, environment, and HIV infection on body composition in adults.

BACKGROUND: The factors that control body composition in disease are uncertain. OBJECTIVE: We planned to compare the relative influences of HIV infection, sex, race, and environment on body composition. METHODS: We analyzed results of body composition studies performed by bioelectrical impedance analysis in 1415 adults from 2 cohorts: white and African American men and women from the United States, and African men and women (279 HIV-infected and 1136 control). The effects of sex and HIV infection on weight, body cell mass, and fat-free mass were analyzed by using both unadjusted and age-, weight-, and height-adjusted data. RESULTS: Control men weighed more and had more body cell mass and fat-free mass than did control women, although control women had more fat. The strongest correlates with body composition were height and weight, followed by sex. HIV infection, age, environment, and race. Control men and women weighed more and had more body cell mass, fat-free mass, and fat than did HIV-infected men. However, differences in body composition between HIV-infected and control groups were strongly influenced by sex. Of the differences in weight between HIV-infected and uninfected subjects, fat-free mass accounted for 51% in men but only 18% in women, in whom the remainder was fat. Sex effects were similar in African and American groups. CONCLUSIONS: Sex has a marked effect on the changes in body composition during HIV infection, with women losing disproportionately more fat than men. Sex-related differences in body composition were narrower in the HIV-infected groups. Race and environment had smaller effects than sex and HIV infection.

Cytomegalovirus colitis and wasting.

Disseminated cytomegalovirus (CMV) infection is associated with significant and progressive depletion of body cell mass and body fat in patients with the acquired immune deficiency syndrome (AIDS). In a study examining the effect of ganciclovir on wasting in AIDS patients with disseminated CMV infection, it was found that patients receiving ganciclovir had significant improvement in such variables as body cell mass, body fat, body weight, and total body energy content when compared with those not receiving ganciclovir. The repletion of body cell mass observed in AIDS patients with disseminated CMV infection who are successfully treated with ganciclovir appears to be associated with improved quality of life and prolongation of survival.

Clinical syndromes associated with microsporidiosis.

Microsporidia are ubiquitous in nature. Several clinical syndromes have been associated with microsporidiosis, especially in HIV-infected individuals, and include enteropathy, keratoconjunctivitis, sinusitis, tracheobronchitis, encephalitis, interstitial nephritis, hepatitis, cholecystitis, osteomyelitis, and myositis. Diarrhea and malabsorption are the most common clinical problems. Enterocytozoon bieneusi is the most common microsporidial cause of intestinal disease. A second species, Encephalitozoon intestinalis (originally named Septata intestinalis) is associated with disseminated as well as intestinal disease. Microsporidiosis has been seen worldwide, and is recognized as a frequent enteric infection in patients with AIDS. The pathogenesis of intestinal disease is related to excess death of enterocytes as a result of cellular infection. Clinically, microsporidiosis most often presents with diarrhea and weight loss as a result of small intestinal injury and malabsorption. However, microsporidia have been detected in virtually all organs, and may provoke symptoms related to their specific localization. The diagnosis of microsporidiosis is made histologically, either from tissue biopsies or secretions. While transmission electron microscopy was required for diagnosis in the past, special stains and light microscopy, as well as immunohistochemical and molecular techniques are capable of providing a firm diagnosis. Therapeutic options are limited. Enc. intestinalis responds well to albendazole, while no antiparasitic therapy has documented efficacy in Ent. bieneusi infections.

Human immunodeficiency virus-related wasting: malabsorption syndromes.

Diarrhea and malabsorption are common findings in patients with the acquired immunodeficiency syndrome (AIDS). The pathogenesis and consequences of malabsorption in human immunodeficiency virus (HIV) infection are similar to those found in non-HIV-related conditions, and are related to both direct intestinal damage and alterations in the coordination of the body's response to feeding. The pathogenesis of malabsorption is multifactorial and includes primary enterocyte injury with partial villus atrophy and crypt hyperplasia, ileal dysfunction with bile salt wasting and fat malabsorption, and exudative enteropathy. Clinical studies show that intestinal cryptosporidiosis leads to excess fecal losses of about 20% for protein and fat. The consequences of malabsorption include decreased appetite; "enterogastrone" effects including dry mouth, decreased gastric acid secretion, decreased rate of gastric emptying, and slowed intestinal transit; anemia resulting from iron, folate, or vitamin B12 malabsorption; and metabolic effects including osteomalacia, gallstones, renal stones, and hypocholesterolemia. Few studies of nutritional therapy have been applied specifically to AIDS patients with malabsorption. Total parenteral nutrition promotes weight gain, although the response to this therapy depends on the underlying clinical problem, with body cell mass repletion noted in patients with malabsorption but predominantly fat gain in patients with systemic infections. Nutritional stabilization also was noted in response to oral administration of a semielemental diet.