Abstract Background Clinical outcomes differ substantially between patients with Crohn’s disease and there is variability in how newly-diagnosed patients are managed. Recent interest has focused on developing biomarkers to predict outcomes and guide therapy. PROFILE was designed to evaluate the clinical utility of a blood-based prognostic biomarker in patients randomised to "top-down" or "accelerated step-up" treatment strategies for newly-diagnosed Crohn’s disease. Methods PROFILE (PRedicting Outcomes For Crohn's dIsease using a moLecular biomarker, ISRCTN 11808228) was an open-label, biomarker-stratified, randomised controlled trial. It enrolled adults with newly-diagnosed active Crohn’s disease (Harvey Bradshaw Index ≥7 and C-reactive protein > upper limit of normal or faecal calprotectin ≥200 ug/g, plus endoscopic evidence of active inflammation) in 40 UK hospitals. Following biomarker testing patients were randomised to "top-down" (infliximab/immunomodulator) or "accelerated step-up" (conventional) treatment stratified by: biomarker subgroup (termed IBDhi/IBDlo), endoscopic inflammation (mild/mod/severe) and extent (colonic/other). The primary endpoint was sustained steroid and surgery-free remission to week 48. The key secondary endpoint was endoscopic remission (absence of ulcers). The full analysis population (equivalent to ‘intention-to-treat’) was analysed. Results 386 patients were randomised from 29 December 2017 to 5 January 2022. Median time from diagnosis to trial enrollment was 12 days (0-191). Primary outcome data were available for 379 eligible participants. Sustained steroid and surgery-free remission was significantly more frequent in "top-down" (79% of 189 patients) compared to the "accelerated step-up" arm (15% of 190 patients), with an absolute difference of 64% (95% CI=57-72%, p<0.001). There was no biomarker-treatment interaction effect (absolute difference 1%, 95% CI=-14 - +14%, p=0.944). Endoscopic remission at week 48 was greater in "top-down" vs "accelerated step-up" (67% vs 44%, 95% CI=11-36%, p<0.001), with no biomarker-treatment interaction. Incidence of adverse events (including disease flares) and serious adverse events was lower in "top-down" vs "accelerated step-up" (168 vs 315; 16 vs 25 respectively), with fewer complications requiring abdominal surgery (1 vs 10, odds ratio=0.095, 95% CI=0.001-0.505) and no increase in infections. Conclusion "Top-down" treatment with combination infliximab/immunomodulator achieved substantially higher sustained steroid and surgery-free remission compared to "accelerated step-up". The biomarker did not show clinical utility in PROFILE. "Top-down" should now be considered standard-of-care for patients with newly-diagnosed active Crohn’s disease.

Objective As the pro‐inflammatory cytokine tumour necrosis factor‐alpha is greater in microsporidiosis than cryptosporidiosis, there may be a distinct metabolic response between the two organisms. Design Male HIV seropositive subjects with an untreated AIDS‐defining diagnosis of microsporidiosis or cryptosporidiosis had measurement of oxygen consumption and carbon dioxide production by indirect calorimetry and body composition analysis to express resting energy expenditure (REE) and substrate oxidation per kilogram of metabolically active tissue. Methods Resting energy expenditure (REE), non‐protein respiratory quotient (NPRQ), fat and carbohydrate oxidation were calculated from respiratory gas analysis. Fat, fat‐free and appendicular muscle masses were measured by dual‐energy X‐ray absorptiometry. Subjects with protozoal diarrhoea were compared to other newly diagnosed, active opportunistic infections. Controls were asymptomatic HIV‐seropositive men matched by peripheral CD4 count. Results Seven subjects with microsporidiosis and six with cryptosporidiosis were compared with 24 subjects with other AIDS‐defining diagnosis (Pneumocystis carinii pneumonia, cytomegalovirus enteritis and Mycobacterium avium‐intracellulare) and 10 controls free from secondary infection. Subjects with cryptosporidiosis had a decreased REE, a significantly increased NPRQ (P< 0.05), decreased fat oxidation (P < 0.05) and increased carbohydrate oxidation compared to microsporidiosis. Subjects with other AIDS diagnoses had an increased REE ( P < 0.01) and fat oxidation and decreased carbohydrate oxidation compared to cryptosporidiosis, and a similar metabolic response to microsporidiosis. Conclusions The metabolic response to cryptosporidiosis differs from microsporidiosis and associated weight loss may be mediated by different mechanisms. Metabolism in other AIDS diagnoses, including microsporidiosis, is compatible with a cachectic response.

BACKGROUNDGastrointestinal symptoms are distressing features of human immunodeficiency virus (HIV) infection, and management is often empirical, including withdrawal of dietary lactose. We assessed the prevalence and severity of intestinal disaccharidase deficiency in vitro and in vivo.METHODSFifty-four HIV-seropositive patients (19 HIV well +/- mild diarrhoea, 7 acquired immunodeficiency syndrome (AIDS) well, and 28 AIDS with diarrhoea) were studied with a combined non-invasive absorption-permeability-disaccharidase test that enables quantitative assessment of the rate of intestinal hydrolysis of lactose, sucrose, and palatinose. Thirty patients had jejunal biopsy specimens suitable for histomorphometric assessment, and 36 had in vitro disaccharidase activity measurement.RESULTSPatients with HIV (with mild diarrhoea) and AIDS (with and without severe diarrhoea) had frequent but mild histomorphometric changes in jejunal specimens. This was associated with frequent (21%-100%) and often severe in vitro jejunal disaccharidase deficiency. In vivo hydrolysis of lactose, sucrose, and palatinose was impaired in 25%-75% of patients, apart from HIV well patients, who were normal. The prevalence of the in vivo lactase and sucrase deficiency was significantly (P < 0.006) lower than in vitro and severe in about 30%.CONCLUSIONSIntestinal disaccharidase deficiency is common both in vitro and in vivo in HIV-seropositive patients but sufficiently severe to consider lactose withdrawal only in about a quarter of the patients with AIDS and diarrhoea.

Although several studies have documented intra- and extracellular glutathione (GSH) deficiency in asymptomatic human immunodeficiency virus (HIV) infection, the mechanisms responsible for the altered GSH homeostasis remain unknown. To determine whether decreased synthesis contributes to this alteration of GSH homeostasis, a primed-constant infusion of [ 2 H 2 ]glycine was used to measure the fractional and absolute rates of synthesis of GSH in five healthy and five symptom-free HIV-infected subjects before and after supplementation for 1 wk with N-acetylcysteine. The erythrocyte GSH concentration of the HIV-infected group was lower ( P < 0.01) than that of the control group (1.4 ± 0.16 vs. 2.4 ± 0.08 mmol/l). The smaller erythrocyte GSH pool of the HIV-infected group was associated with a significantly slower ( P < 0.01) absolute synthesis rate of GSH (1.15 ± 0.14 vs. 1.71 ± 0.15 mmol ⋅ l −1 ⋅ day −1 ) compared with controls. Cysteine supplementation elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte GSH. These results suggest that the GSH deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage in cysteine availability.

BACKGROUND Diarrhoea in AIDS is associated with anorexia and weight loss. The importance of gastrointestinal transit in such symptoms has not been addressed. AIMS To assess jejunal to caecal transit times in subjects with AIDS related diarrhoea and weight loss and correlate these with measures of absorptive capacity and intestinal permeability. METHODS Jejunal to caecal transit times were assessed in 20 seronegative controls and 60 HIV seropositive subjects from serum analysis of 3-O-methyl-d-glucose and sulphapyridine after ingestion of the monosaccharide and sulphasalazine in aqueous solution. The method also allows an estimation of gastric emptying times for liquids. Intestinal absorptive capacity and permeability were assessed by a combined test using 3-O-methyl-d-glucose, d-xylose,l-rhamnose, and lactulose. RESULTS Gastric emptying was significantly delayed in all groups of patients with AIDS. Mean jejunal to caecal transit times were not significantly different between controls (246 (62) minutes) and patients without diarrhoea (AIDS, well: 278 (103) minutes; AIDS, wasting: 236 (68) minutes), cytomegalovirus colitis (289 (83) minutes), pathogen negative diarrhoea (192 (100) minutes), or microsporidiosis (190 (113) minutes), although 30% of patients had values below the control range. Patients with cryptosporidiosis differed significantly from controls (135 (35) minutes, p<0.0001), seven of 10 having rapid transit times. Absorptive capacity was reduced and intestinal permeability significantly increased in AIDS, but did not correlate significantly with transit times. CONCLUSION Small bowel transit is accelerated in many patients with AIDS, particularily in protozoal diarrhoea, but is not the sole explanation for malabsorption of monosaccharides.

Although several studies have shown that asymptomatic human immunodeficiency virus infection elicits an increase in whole body protein turnover, it is not known whether this increased protein turnover includes changes in the kinetics of acute-phase proteins (APPs). To answer this question, we measured 1) the plasma concentrations of four positive (C-reactive protein, alpha1-antitrypsin, haptoglobin, and fibrinogen) and four negative APPs [albumin, high-density lipoprotein (HDL)-apolipoprotein (apo) A1, transthyretin, and retinol-binding protein] and 2) the fractional (FSR) and absolute (ASRs) synthesis rates of three positive and three negative APPs using a constant intravenous infusion of [2H5]phenylalanine in five subjects with symptom-free acquired immunodeficiency syndrome (AIDS) and five noninfected control subjects. Compared with the values of the controls, the plasma concentrations, FSRs, and ASRs of most positive APPs were higher in the AIDS group. The negative APPs had faster FSRs in the AIDS group, there was no difference between the ASRs of the two groups, and only HDL-apoA1 had a lower plasma concentration. These results suggest that symptom-free AIDS elicits an APP response that is different from bacterial infections, as the higher concentrations and faster rates of synthesis of the positive APPs are not accompanied by lower concentrations and slower rates of synthesis of most of the negative APPs.

HIV+ individuals with human CMV (HCMV) reactivation have a CD3 receptor-mediated T cell hyporesponsiveness when compared with CD4-matched HIV+ and HCMV- control groups. The impairment of proliferation was not reversed by exogenous IL-2. A typical increase in NFkappaB expression was observed following cross-linking of the CD3 receptor, but did not lead to increased CD25 cell surface expression or cell proliferation. The HCMV-induced non-responsiveness was not observed when cells were stimulated with phorbol esters. Lymphocytes cultured with media collected from cell cultures infected with HCMV showed a dose-dependent inhibition in the total T cell population even though cells staining dually for CD8/57 increased in number. The altered growth factor requirements of CD8/57+ cells may therefore account for their presence in AIDS and patients following bone marrow transplantation.

Extrapolation of data from energy balance studies in HIV-seropositive men to HIV-seropositive women may be inaccurate due to gender differences in body composition, hormones and metabolism. If women have a different metabolic response to the human immunodeficiency virus (HIV), nutritional advice may differ from HIV-seropositive men. Ten asymptomatic HIV-seropositive women were matched with 10 heterosexual female controls from low-risk groups. Subjects and controls had assessment of energy and protein intake, resting energy expenditure (REE) and substrate oxidation, small bowel absorption and permeability and body composition. There were no significant differences in REE, substrate oxidation and body composition. Energy and protein intake and small bowel permeability were increased and sugar absorption decreased in HIV-seropositive women (all P 0.05). Unlike asymptomatic HIV-seropositive men, asymptomatic HIV-seropositive women do not have significant alterations in metabolism or body composition. Therefore, nutritional advice may need to vary according to the gender of the asymptomatic HIV-seropositive subject. <

Background: Changes in body weight and lean tissue increase morbidity and mortality during AIDS; however there are few data on the effect of alterations in nutrition and metabolism on disease progression at earlier stages of HIV infection.Objectives: To assess whether change in weight, lean tissue or skeletal muscle affects progression to AIDS; to assess prospectively the effects of recognized alterations in nutrition and metabolism in asymptomatic HIV-seropositive men on disease progression; and to examine prospectively changes in nutrition and metabolism at AIDS-defining diagnosis.Methods: A group of 104 asymptomatic HIV-seropositive men were recruited and prospectively examined at 3-monthly intervals between April 1993 and September 1995. Nutritional status and metabolism were examined using indirect calorimetry, dual energy X-ray absorptiometry and urine excretion of simple sugars. Time-fixed and time-dependent Cox's proportional hazard models were fitted to calculate risks of developing a first AIDS diagnosis, weight loss or death.Results: During the study period, 31 subjects had a first AIDS diagnosis of whom 26 were fully assessed. Changes in nutrition and metabolism do not affect disease progression in asymptomatic HIV infection. However, subjects with a reduction in body weight and basal metabolic index tend to have a higher risk of progression to AIDS-defining diagnosis, independent of CD4 count. There is a significant decrease in all body tissue compartments, a decrease in excretion of urinary sugars and significant increase in resting energy expenditure and fat oxidation associated with a first AIDS diagnosis.Conclusion: Change in metabolic and nutritional status at the asymptomatic stage of HIV infection does not influence disease progression significantly, although there is a trend suggesting weight loss has an independent effect on outcome. There is a cachectic response to AIDS-defining opportunistic infection or tumour. (C) 1999 Lippincott Williams & Wilkins.

BACKGROUND & AIMS:Microsporidiosis is a common cause of chronic diarrhea in human immunodeficiency virus (HIV)-seropositive individuals and often does not respond to treatment. Fecal tumor necrosis factor alpha (TNF-alpha) is elevated in microsporidiosis; therefore, thalidomide, an anti-TNF-alpha agent, was used as therapy.METHODS:Eighteen subjects with chronic diarrhea caused by Enterocytozoon bieneusi that had not responded symptomatically to albendazole and 1 untreated subject with Encephalitozoon intestinalis received 1 month of thalidomide, 100 mg nocte. Clinical response was assessed by stool frequency and body weight, histological response by light microscopy with villus height/crypt depth ratios and electron microscopy, and immunologic response by fecal TNF-alpha level.RESULTS:Seven subjects with chronic diarrhea due to E. bieneusi had a complete clinical response, and 3 had a partial response to thalidomide. There was a significant decrease in stool frequency from 5.3 to 3.1 per day (P = 0.001), and weight increased significantly by 1.2 kg (P < 0.02). Thalidomide significantly increased the villus height/crypt depth ratio (1.95 to 2.07; P = 0.045) and number of abnormal forms of microsporidia (P < 0.01). Fecal TNF-alpha level nonsignificantly decreased from 17.9 to 8.9 U/mL. There was apparent disruption of all stages of the life cycle of E. intestinalis.CONCLUSIONS:Thalidomide may be an effective therapy for diarrhea and weight loss from E. bieneusi.

Hypoalbuminaemia and diarrhoea are common complications of HIV infection and substantial causes of morbidity, but the specific intestinal pathologies that cause enteric protein loss have not been clearly defined. Two hundred and twenty stool samples from patients with a variety of HIV related conditions were analysed for faecal alpha 1 antitrypsin. Patients with intestinal Kaposi's sarcoma had a significantly raised faecal alpha 1 antitrypsin value and hypoalbuminaemia. A faecal alpha 1 antitrypsin value of greater than 0.3 mg/g wet stool has a sensitivity of 94% and a specificity of 76% for the diagnosis of intestinal Kaposi's sarcoma in HIV positive individuals. Patients with cytomegalovirus and bacterial enteritis had raised faecal alpha 1 antitrypsin values but levels were normal for all other intestinal pathologies compared with pathogen negative stool. The combination of faecal alpha 1 antitrypsin concentration greater than 0.2 mg/g, a negative stool culture for enteric bacteria, and the absence of palatal Kaposi's sarcoma has a sensitivity of 55% and specificity of 88% for the diagnosis of enteric cytomegalovirus infection.

Departments of HIV/GUM and Immunology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9TH, UK.