Crofelemer, a novel agent for treatment of non-infectious diarrhea in HIV-infected persons.

Crofelemer is the first US FDA-approved drug for symptomatic relief in HIV-infected persons on antiretroviral therapy (ART) who have non-infectious diarrhea. With the availability of ART, there is increased survival and decrease in gastrointestinal opportunistic infections. However, diarrhea secondary to ART and HIV enteropathy is common in HIV-infected persons. Crofelemer is manufactured from the red latex sap of the Croton lechleri tree in South America. It has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea. Crofelemer is well tolerated due to minimal systemic absorption and has a good safety profile. The availability of crofelemer will likely have a positive impact on the quality of life in HIV-infected persons and also increase compliance to ART.

Differential metabolic response in AIDS-related chronic protozoal diarrhoea.

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.

Urinary recovery of lactulose compared to D-xylose absorption kinetics in HIV patients with diarrhea and weight loss.

Using a kinetic model of D-xylose absorption, we have previously shown that there is severely impaired absorption of D-xylose in HIV patients with diarrhea and weight loss. The absorptive defect is characterized by an increased rate constant for nonabsorptive loss of D-xylose, Ko, and a decreased absorptive rate constant, Ka, and is unrelated to histology or the presence of pathogens. It is not known if there is also abnormal paracellular transport in these patients. We have extended our observations in these patients by including a measurement of paracellular transport, lactulose absorption. Nine HIV patients with chronic diarrhea, weight loss, and no detectable intestinal pathogens, two healthy volunteers, and three non-HIV patients with chronic diarrhea (two functional and one with scleroderma) were enrolled. Of the nine HIV patients, six had diminished bioavailability of D-xylose, F (range: 19-52%, normal >70%), and elevated rate constant for nonabsorptive loss, Ko (range: 0.54-1.35/hr, normal <0.353/min). Four of the six also had decreased Ka (range: 0.09-0.36/hr, normal >0.634/min). Only one of these six had increased lactulose recovery (3.51%, normal <0.5%). Two of three patients with normal kinetic parameters of D-xylose absorption had increased lactulose urinary recovery (1.92%, 2.61%). In conclusion, lactulose absorption is increased in some patients with HIV-related diarrhea who have normal D-xylose absorption, suggesting a paracellular mechanism for diarrhea in some patients with AIDS enteropathy.

Changes in parietal cell structure and function in HIV disease.

The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric mucosa were evaluated in patients with early and late HIV infection (AIDS) and compared to non-HIV-infected controls. Immunolocalization of HIV-related antigens in gastric mucosa was also examined. Fasting gastric juice pH and intrinsic factor (IF) concentration in AIDS and HIV infected subjects were significantly different from controls (P = 0.012 and P = 0.025, respectively for pH, and 0.029 and 0.035 for IF; ANOVA LSD test). By contrast, maximal acid output (MAO) was significantly lower in AIDS, but not HIV-infected subjects (P = 0.043 and P = 0.322, respectively). Similarly, Schilling test phases 1 and 2 results were significantly lower in AIDS, but not HIV-infected subjects. Varying degrees of vacuolar degeneration of parietal cells were seen on light microscopy. On electron microscopy (EM), tubulovesicles were reduced and intracellular canaliculi dilated with striking loss of microvilli. Immunofluorescent staining with antibodies to gp120, gp41, p24, and p17 demonstrated positive punctate signals in the cytoplasm of gastric glands, which includes parietal cells. Immunogold EM with anti-gp120, localized predominantly to the microvilli of intracellular canaliculi in parietal cells. Abnormal secretory function of parietal cells occurs early in HIV disease, affects acid as well as intrinsic factor secretion, and is associated with morphological changes in the acid secretory apparatus.

Bile acid malabsorption in HIV infected patients with chronic diarrhoea.

AIMS: To look for the presence of bile acid malabsorption in HIV infected patients with chronic diarrhoea and determine whether bile sequestering agents may have a role in palliating this common problem. METHODS: Nineteen HIV infected patients with chronic diarrhoea (duration > one month) poorly controlled on conventional treatment were investigated using the seven day retention of 75seleno-23-homocholic acid taurine (SeHCAT) as a measure of bile acid loss from the enterohepatic circulation. Patients with evidence of bile acid malabsorption were offered cholestyramine. RESULTS: Sixteen (84%) had evidence of bile acid malabsorption (< 15% retention at seven days). Ten of the 16 patients with bile acid malabsorption had terminal ileal biopsies-six had ileitis and four normal histology, suggesting that malabsorption is not always related to terminal ileitis. Thirteen patients with bile acid malabsorption have been treated with cholestyramine and 11 have reported a symptomatic response. CONCLUSIONS: Bile acid malabsorption can be demonstrated in some cases of HIV associated chronic diarrhoea and we suggest a therapeutic trial of a bile sequestering agent in patients whose symptoms are not well controlled using conventional anti-diarrhoeal agents.

HIV-enteropathy and bile acid malabsorption: response to cholestyramine.

Chronic diarrhea and weight loss are common in patients with AIDS. We report on an AIDS patient with chronic diarrhea, steatorrhea, and marked weight loss. A 75SeHCAT test demonstrated that the diarrhea was mainly due to bile acid malabsorption. Therapy with cholestyramine dramatically reduced bowel movements and led to significant reversal of weight loss.