Switch to raltegravir decreases soluble CD14 in virologically suppressed overweight women: the Women, Integrase and Fat Accumulation Trial.

OBJECTIVES: Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: HIV-infected women with central adiposity and HIV-1 RNA < 50 HIV-1 RNA copies/mL continued their thymidine-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma. RESULTS: Of the 37 evaluable subjects, 78% were non-White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m(2) and the median CD4 count was 558 cells/µL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL [-21% (P < 0.001) vs. PI/NNRTI -5% (P = 0.49); between-group P < 0.01]. After 48 weeks, immediate-switch subjects maintained this decline and delayed-switch subjects experienced a similar decline following the switch to RAL (-10%; within-group P < 0.01). Immediate-switch subjects also experienced an initial increase in tumour necrosis factor (TNF)-α that was neither maintained after 48 weeks nor seen in delayed-switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant. CONCLUSIONS: In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.

Pilot randomized trial of nutritional supplementation in patients with tuberculosis and HIV-tuberculosis coinfection receiving directly observed short-course chemotherapy for tuberculosis.

OBJECTIVE: To investigate the effects of nutritional supplementation on the outcome and nutritional status of south Indian patients with tuberculosis (TB) with and without human immunodeficiency virus (HIV) coinfection on anti-tuberculous therapy. METHOD: Randomized controlled trial on the effect of a locally prepared cereal-lentil mixture providing 930 kcal and a multivitamin micronutrient supplement during anti-tuberculous therapy in 81 newly diagnosed TB alone and 22 TB-HIV-coinfected patients, among whom 51 received and 52 did not receive the supplement. The primary outcome evaluated at completion of TB therapy was outcome of TB treatment, as classified by the national programme. Secondary outcomes were body composition, compliance and condition on follow-up 1 year after cessation of TB therapy and supplementation. RESULTS: There was no significant difference in TB outcomes at the end of treatment, but HIV-TB coinfected individuals had four times greater odds of poor outcome than those with TB alone. Among patients with TB, 1/35 (2.9%) supplemented and 5/42(12%) of those not supplemented had poor outcomes, while among TB-HIV-coinfected individuals, 4/13 (31%) supplemented and 3/7 (42.8%) non-supplemented patients had poor outcomes at the end of treatment, and the differences were more marked after 1 year of follow-up. Although there was some trend of benefit for both TB alone and TB-HIV coinfection, the results were not statistically significant at the end of TB treatment, possibly because of limited sample size. CONCLUSION: Nutritional supplements in patients are a potentially feasible, low-cost intervention, which could impact patients with TB and TB-HIV. The public health importance of these diseases in resource-limited settings suggests the need for large, multi-centre randomized control trials on nutritional supplementation.

Nutritional supplementation in HIV-infected individuals in South India: a prospective interventional study.

BACKGROUND: Malnutrition in human immunodeficiency virus (HIV)-infected individuals is associated with faster disease progression, higher mortality rates, and suboptimal response to antiretroviral therapy (ART). METHODS: We conducted a prospective interventional study to evaluate the effects of an oral macronutrient supplement among HIV-infected adults in South India. Patients attending Tuberculosis Research Centre clinics from June 2005 through December 2007 had baseline nutritional assessment and laboratory investigations performed. Patients at 1 center received nutritional counseling and standard care, whereas patients at 2 centers additionally received a macronutrient providing 400 cal and 15 g of protein daily. Study outcomes were changes in anthropometry, body composition, blood chemistry, and immune status at 6 months. RESULTS: In total, 636 ART-naive patients were enrolled in the study; 361 completed 6 months of follow-up (282 received supplements and 79 received standard care). Mean age +/- standard deviation (SD) was 31 +/- 7 years, mean weight +/- SD was 50 +/- 10 kg, and 42% were male. Significant increases in body weight, body mass index, midarm circumference, fat-free mass, and body cell mass were observed in the supplement group but not in the control group at 6 months; gains were greater in patients with CD4 cell counts <200 cells/microL. No changes were observed in lipid levels, whereas the CD4 cell count decreased in the control group. However, after adjusting for baseline differences, these changes were not statistically significantly different between the groups. CONCLUSIONS: Macronutrient supplementation did not result in significantly increased weight gain compared with standard care (including nutritional counseling) among patients with moderately advanced HIV disease. The effect of supplementation on specific subsets of patients and on preserving immune function needs further research.

Nutrition and HIV infection: review of weight loss and wasting in the era of highly active antiretroviral therapy from the nutrition for healthy living cohort.

Despite major advances in the treatment and survival of patients infected with human immunodeficiency virus (HIV), weight loss and wasting remain common problems. In the HIV-infected population, weight loss is associated with lower CD4+ cell counts and is an independent predictor of mortality. The etiology of weight loss and wasting is complex and multifactorial. We discuss, on the basis of a large longitudinal cohort that examined nutritional status in HIV infection, data on weight loss and wasting from the present clinical era. The definition, prevalence, and significance of HIV-associated weight loss and wasting are summarized. The etiology of weight loss is discussed for 2 main categories: inadequate nutrient intake and altered metabolism. Finally, studies of interventions to treat HIV-associated weight loss and wasting are discussed. This information is intended to raise awareness among health care providers of HIV-infected patients that weight loss and wasting remain important acquired immunodeficiency syndrome-defining conditions, despite the advent of HAART.

Diagnostic strategies in HIV-infected patients with diarrhea.

PIP: Infectious disease specialists have proposed guidelines on diagnostic evaluation of HIV infected patients with diarrhea. They are based on using clues from a careful history, physical examination, and evaluation of known laboratory data. Early on, clinicians must differentiate between small and large bowel diarrhea to properly evaluate any patient with diarrhea. If available, they should use the patient's absolute CD4 count, duration of diarrhea, frequency and characteristics of stools, degree of weight loss, and exposure history (e.g., residence and water supply). When conducting the patient history, clinicians should ask about recent antibiotic or antiretroviral use, previous opportunistic infections, and other illnesses or hospitalizations. The physical exam should include height and weight, orthostatic blood pressure, and degree of wasting. Abnormalities of skin and mucous membrane may indicate nutrient deficiencies (e.g., vitamin B deficiency = stomatitis). The disease specialists provide us with an algorithm to the diagnostic evaluation of HIV infected patients with diarrhea using the CD4 cell count and the type of diarrhea (small or large bowel) as the defining factors. For example, clinicians should request stool cultures for Salmonella, Campylobacter, and Yersinia and examination with saline and iodine for the presence of ova and parasites for patients with CD4 counts greater than 200 cells x 1 million/l and small bowel diarrhea. If the patient also has a fever, blood cultures should be done to test for Salmonella. If all these tests are negative and the patient still has symptoms, modified acid-fast staining should be done to look for cryptosporidium oocysts. If this test is negative and symptoms continue, upper endoscopy with biopsy is warranted. This strategy should result in a less time-consuming and more directed diagnostic strategy that may improve quality of life.^ieng

Malabsorption and wasting in AIDS patients with microsporidia and pathogen-negative diarrhea.

OBJECTIVE: To define the clinical syndrome, nutritional status and malabsorptive status in patients with HIV and chronic diarrhea and either microsporidia or no identified pathogen. PATIENTS: HIV-positive patients from an urban, hospital-based infectious disease clinic with chronic diarrhea who had undergone exhaustive gastrointestinal and stool studies for enteric pathogens and were found to have either microsporidia or no pathogen. METHODS: Patients were evaluated for clinical history, physical, body composition, nutritional and malabsorptive studies including D-xylose, Schilling test, determinations of 24 h stool fat, weight and nitrogen, and 24 h urea nitrogen. RESULTS: Ten patients with microsporidia were studied, four of whom were infected with Septata intestinalis, six with Enterocytozoon bieneusi; nine patients had no identified pathogen. Patients in both groups were comparable in stage of HIV disease, and demonstrated abnormal nutritional status and malabsorptive parameters. Patients with no pathogen had significantly longer duration of symptoms prior to presentation; however, patients with microsporidia had significantly greater malabsorption of fat, D-xylose, vitamin B12, and significantly lower serum levels of zinc. Nutritional status and malabsorption were similarly depressed in patients infected with either species of microsporidia. CONCLUSION: HIV-infected patients with chronic diarrhea associated with either microsporidial infection or with no identified pathogen had abnormal parameters of absorption and malnutrition, and those infected with microsporidia demonstrated more severe malabsorption.

Physiological effects of HIV infection on human intestinal epithelial cells: an in vitro model for HIV enteropathy.

OBJECTIVES: To determine the role of direct infection of intestinal cells with HIV-1 in the pathogenesis of HIV-related enteropathy. METHODS: We infected HT-29-18-C1 intestinal cells with the IIIB strain of HIV and examined the physiologic effects of enterocyte function. Dipeptidase-IV, aminopeptidase-N, gamma glutamic transferase, and alkaline phosphatase were measured in HIV-infected and control cultures. The cellular second messengers intracellular calcium and cyclic adenosine monophosphate were also measured in infected and control cultures. RESULTS: A persistent infection was established for > 95 days with peak supernatant reverse transcriptase and HIV p24 antigen levels of 5.17 log10 c.p.m./ml and 45 ng/ml, respectively. Brush-border enzyme activity (nmol of product/min/mg protein) tended to be lower in infected cell cultures compared with controls early in infection (P < 0.02). Baseline second messenger concentrations were similar but infected cultures responded to stimulation with a calcium ionophore with an exaggerated increase in intracellular calcium (P = 0.03). CONCLUSIONS: These results suggest that absorptive and secretory function of enterocytes may be altered by direct HIV infection and that additional physiologic experiments with this in vitro model may lead to a better understanding of the clinical syndrome of HIV enteropathy.

HIV-1 Tat modulates invasion by a bacterial enteric pathogen into a human intestinal cell line.

OBJECTIVE: To explore the possibility that an HIV-1 gene product may modulate entry of an invasive enteric pathogen into a terminally differentiated human intestinal cell line. HIV-1 Tat was selected for investigation because of its unique ability to cross cell membranes. METHODS: After transient transfection of HT29-C1 cells with plasmids containing HIV-1 long terminal repeat (LTR)-lacZ plus a Tat expression cassette, or with a pSR-lacZ control plasmid, bacterial invasion assays were performed on both groups of cells utilizing a clinical Salmonella isolate. Assays were performed concurrently on a control group of non-transfected cells. A second series of experiments compared bacterial invasion into cells transfected with the Tat expression vector alone versus cells transfected with either an isogenic expression vector that did not make Tat, or with pSR-lacZ. Finally, the ability of exogenous Tat protein to transactivate an HIV-1 LTR-chloramphenicol acetyltransferase (CAT) plasmid which had been transfected into HT29-C1 cells and to modulate Salmonella invasion was also assessed. RESULTS: HT29-C1 cells transfected with a Tat expression vector, either alone or in combination with another plasmid, were significantly less susceptible to bacterial invasion than cells that either did not undergo transfection, were transfected with an otherwise isogenic expression vector without Tat, or transfected with an unrelated plasmid. Duplicate experiments also demonstrated that exogenous purified Tat protein transactivated an HIV-1 LTR-CAT plasmid which had been transfected into HT29-C1 cells and inhibited Salmonella invasion compared with unexposed cells. CONCLUSION: HIV-1 Tat inhibits Salmonella invasion of a human enterocyte cell line whether the protein is expressed intracellularly or provided exogenously.

Role of acquired immune deficiency syndrome-defining conditions in human immunodeficiency virus-associated wasting.

To evaluate the contribution of acquired immune deficiency syndrome-defining conditions (ADCs) in human immunodeficiency virus (HIV)-associated wasting, we analyzed longitudinal data from 671 participants in a nutrition and HIV cohort study. Data on ADCs, height, and weight were collected at baseline and during 6 monthly study visits. The frequency of ADCs decreased over time, but the relative risk (RR) of wasting (decrease in body mass index [BMI] to <20 kg/m(2)) increased with a history of >1 ADC; the RR of wasting increased 1.3-fold with each additional historical ADC. Any ADC during the 6 months prior to a study visit was associated with a decrease in BMI to <20 kg/m(2). The risk of wasting increased 2.7-fold with each additional recent ADC. These risks were not altered when adjusted for socioeconomic status, CD4 cell count, energy intake, or baseline BMI. Although ADCs contribute to the development of wasting, their contribution is relatively small.

Cytomegalovirus vasculitis. Case reports and review of the literature.

Cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality among immunocompromised patients. It may present with a mild, self-limited syndrome, retinitis, colitis, or invasive disease with pneumonitis, hepatitis, and bone marrow suppression. We review another, less common manifestation of CMV disease: CMV-associated vasculitis. CMV may productively infect vascular endothelial cells (25), causing a local vasculitis (3, 14, 19) and ischemia. Alternatively, the host immune response to cells expressing viral antigen may be the stimulus for vasculitis (12, 53). Since there are no pathognomonic appearances to mucosal or cutaneous lesions, biopsy of accessible sites is critical for diagnosis and expeditious initiation of appropriate antiviral therapy. The CMV-associated vasculitides represent a broad spectrum of diseases, with GI vasculitis in nontransplant recipients having the best prognosis. Cutaneous vasculitis associated with CMV seems to be a more fulminant disease, with the majority of cases having a fatal outcome. These differences likely reflect the degree of viral burden and the state of immune competence. Additionally, since the virus itself is immunosuppressive, host defenses may be further compromised by the infection. Although a large collective experience assessing the impact of ganciclovir and foscarnet is not currently available, both the prompt initiation of antiviral treatment and a concurrent reduction in any immunosuppressive regimen, including steroids, should be undertaken since these therapeutic strategies have clearly improved outcome for other CMV syndromes (22, 34, 55). As the number of recipients rises and the HIV pandemic spreads we are likely to see an increase in the number of cases of vasculitis associated with CMV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential role of adherence traits of Escherichia coli in persistent diarrhea in an urban Brazilian slum.

We examined stools from 40 children with persistent diarrhea (duration, 14 days or more), from 50 children with acute diarrhea and from 38 control children to determine infectious etiologies for persistent diarrhea in Goncalves Dias, an urban favela (slum) in Fortaleza, Ceara, Brazil. Children with persistent diarrhea and children with acute diarrhea had similar rates of isolation of routine viral, bacterial and parasitic enteric pathogens. Routine pathogens were identified in at least 20% of cultures done more than 14 days into the diarrheal illness. We examined Escherichia coli isolated from these stools for adherence potential. Enteroaggregative E. coli were isolated significantly more often from children with persistent diarrhea than from control children or children with acute diarrhea (P less than 0.05). E. coli with hemagglutination patterns suggestive of adherence pili were also isolated more often from children with persistent diarrhea than from children with acute diarrhea (38% vs. 18%; P less than 0.05). Enterotoxigenic E. coli were isolated in combination with rotavirus more often from children with persistent diarrhea than from children with acute diarrhea. E. coli which were hydrophobic or exhibited hemagglutination were also seen more often in association with Giardia in children with persistent diarrhea. These findings suggest that the etiology of persistent diarrhea in children is complex and that the aggregative E. coli are associated with prolonged diarrheal illness. Although routine diarrheal pathogens may be present for more than 14 days, combinations of pathogens, including E. coli with adherence potential, may also contribute to prolonged diarrheal disease.

Viral hepatitis and gastroenteritis transmitted by shellfish and water.

The epidemiology and clinical presentation of water-borne viral diseases, including shellfish-associated viral illnesses, are discussed in this article. Hepatitis A virus, Non A-Non B hepatitis and the agents of viral gastroenteritis, Norwalk agent, Snow Mountain agent, rotavirus, the small round viruses, caliciviruses, and astroviruses are included. The technical problems associated with evaluating the viral contamination of water or shellfish are noted.

Diarrheal disease in patients infected with human immunodeficiency virus in Bangkok, Thailand.

Diarrheal disease and its associated morbidities occur frequently in patients infected with human immunodeficiency virus (HIV) and may be associated with a decreased quality of life. We studied the spectrum of symptoms, measures of nutritional status, and the enteric pathogens associated with diarrheal disease in a group of 24 patients infected with HIV in Bangkok, Thailand compared with a group of 19 patients infected with HIV without diarrhea cared for at the same clinic. Patients with diarrhea appeared to have more advanced disease by CD4 cell counts and complained more frequently of symptoms such as anorexia, gas, and bloating than patients without diarrhea. Patients with diarrhea had a tendency toward a lower nutritional status, as measured by body mass index and mid arm circumference. Stool culture and examination revealed that enteric pathogens including Salmonella species and Cryptosporidium parvum sporidia were recovered at equal frequencies in patients with and without diarrhea (27% of the patients with diarrhea and 25% of the patients without diarrhea). Microsporidia was identified in one patient with diarrhea. It was not possible to identify a pathogen in 73% of the patients with diarrhea and 75% of the patients without diarrhea, suggesting that additional agents or factors may be responsible for the diarrheal symptoms in the patients with diarrhea. More extensive studies to identify potentially treatable pathogens in HIV-infected patients with diarrhea in Thailand are warranted and further attempts to better define the syndrome of pathogen-negative diarrheal disease in patients infected with HIV might result in the development of more targeted interventions in these patients.

Recombinant human tumor necrosis factor and recombinant murine interleukin-1 alter the binding of Escherichia coli to intestine, mucin glycoprotein, and the HT29-C1 intestinal cell line.

Little is known about the effects of cytokines at the intestinal mucosal surface on the adherence of bacteria. We examined the effects of recombinant tumor necrosis factor (TNF) and interleukin-1 (IL-1) on the adherence of various strains of Escherichia coli to intestinal mucosa in vivo and in in vitro models. We studied the effects of TNF or IL-1 injected intraperitoneally on the ability of a rabbit enteric pathogen (RDEC-1) and a nonpathogenic E. coli (1392-) to colonize rabbit small bowel and found that there was a trend toward increased colonization by the RDEC-1 organisms in the TNF-treated rabbits, and a significant increase in colonization by the RDEC-1 organisms in the IL-1-treated animals (P < 0.01). Both TNF and IL-1 altered the density and the level of glycosylation of the small bowel mucus glcoprotein purified from the treated and untreated rabbits, and TNF treatment significantly increased the number of bacteria bound by this purified mucin (P < 0.01 for all strains). HT29-C1 intestinal cells in tissue culture were also grown in media with TNF or IL-1 and used in bacterial binding assays. The cells provided with media with 50 pg/mL of either cytokine bound significantly more of the three bacterial strains than cells in untreated media (P < 0.01 for all strains). The cytokines TNF and IL-1 have the potential to alter bacterial adherence to intestinal mucosa in vivo and in vitro; additional studies to clarify the role that these alterations in adherence may play in the clinical syndromes characterized by increased levels of intestinal cytokines are warranted.

A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea reduces diarrhea and malabsorption: a prospective, controlled trial.

Our objective was to determine whether a medium-chained triglyceride (MCT)-based diet, compared to a long-chain triglyceride (LCT)-based diet, conveys a beneficial effect on diarrhea and fat malabsorption in human immunodeficiency virus (HIV)-infected individuals with chronic diarrhea and weight loss. A secondary objective was to evaluate the pathogens associated with the diarrhea and to evaluate whether the etiologic agent was a determinant of response to the nutritional intervention. Prospective, randomized double-blind comparative trial was conducted in 24 adult patients with HIV, diarrhea of greater than 4-wk duration, fat malabsorption, and loss of 10-20% of ideal body weight, these patients were recruited from our outpatient infectious disease clinic. Evaluations of diarrheal pathogens were made by complete stool examination, upper and lower endoscopy with quantitative culture, and biopsy. Body composition determinations, and measurements of fat, carbohydrate, and vitamin absorption pre- and postintervention. Patients were randomly assigned to one of two complete nutritional products with either medium- or long-chain triglyceride fat exclusively for 12 d followed by treatment of infectious pathogens. Ten patients were found to have Microsporidium and 9 patients had no identifiable pathogen. All patients responded to intervention with both nutritional products overall with 45% fewer stools, decreased stool fat and weight, and a significant increase in urine nitrogen. The group that received the MCT product demonstrated significantly decreased stool number (mean 4 to 2.5), stool fat (mean 14 to 5.4 g), and stool weight (mean 428 to 262 g) compared with baseline (P < 0.01 for all). Patients with both species of microsporidia and with pathogen negative diarrhea had good response. We found that HIV patients with diarrhea, regardless of etiology, and documented fat malabsorption may benefit symptomatically from a diet composed of an MCT-based liquid supplement.

Epidemiology of persistent diarrhea and etiologic agents in Mirzapur, Bangladesh.

To determine the epidemiology and etiologic agents of persistent diarrhea we carried out an intensive diarrhea surveillance on children less than six years old in rural Bangladesh. From March 1987 to February 1989 we examined 363 children through diarrhea recall interviews and analyzed stool samples of all diarrhea cases for potential pathogens. Results showed that children had an average of two episodes per year and the incidence rate of diarrheal episodes defined as acute (< 14 d) and persistent (> or = 14 d) varied similarly with age. The peak incidence (episodes/child/year) of acute diarrhea (2.8) and persistent diarrhea (0.8) occurred in the 6-11 months age group. The data showed that an episode tended to be prolonged if the stool was loose/mucoid or bloody at onset. Aggregative adherent Escherichia coli was found significantly more often at onset in persistent than in acute episodes, whereas Shigella, Aeromonas, Giardia and toxigenic E. coli were isolated with less frequency in persistent than acute episodes. This suggests that other factors might be more important in the development of persistent diarrhea than specific pathogens.

Oral nutrition for the patient with HIV infection.

In the era of highly active antiretroviral therapy, it is unclear what percentage of patients with HIV infection will develop nutritional issues, including weight loss, diarrheal illness and anorexia. The purpose of this article is to discuss nutritional concerns that can occur with HIV infection and potential treatment strategies. We have included 3 case studies identifying these issues and a nutritional assessment guideline. Nutrition interventions, exercise recommendations, and other alternative strategies to combat HIV associated weight loss is discussed.