Gerond Lake-Bakaar

Gastropathy and Ketoconazole Malabsorption in the Acquired Immunodeficiency Syndrome (AIDS)

STUDY OBJECTIVE To correlate oral ketoconazole absorption with gastric acid secretion in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Prospective measurement of maximal acid output and oral ketoconazole absorption with and without 0.1-N hydrochloric acid. SETTING Hospital in-patients in university medical center. PATIENTS Ten consecutive male patients with AIDS. INTERVENTION Maximal acid output was determined after pentagastrin stimulation in all patients. Serum ketoconazole levels were measured the day after ingestion of a 200-mg ketoconazole tablet in the fasted state. On the final day, ketoconazole was ingested with 200 mL of 0.1-N hydrochloric acid. MEASUREMENTS AND MAIN RESULTS Maximal acid output was below 15 mEq/h in 7 of 10 patients. In all 7, the area under the serum ketoconazole concentration-time curve was below normal (1.4 +/- 0.9 mg/h.L; mean +/- SE), and absorption was normalized by hydrochloric acid (9.9 +/- mg/h.L). Two of three patients with maximal acid outputs above 15 mEq/h had normal ketoconazole absorption (15.1 +/- 6.7 mg/h.L). CONCLUSIONS The bioavailability of oral ketoconazole is reduced in patients with AIDS, largely as a result of gastric hypochlorhydria. Ketoconazole tablets should therefore be given with acid in these patients.

Gastric Secretory Failure in Patients with the Acquired Immunodeficiency Syndrome (AIDS)

Excerpt The importance of gastric juice as a barrier to enteric infections has been well established (1, 2). The frequency of gastrointestinal infections and diarrhea in patients with the acquired ...

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 andP=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 andP=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.

Alcohol abuse and stage of HIV disease in intravenous drug abusers.

Our objective was to identify factors that might correlate with human immunodeficiency virus (HIV) disease stage in intravenous drug abusers (IVDA). Particular attention was given to alcohol abuse. We accordingly explored in a cross-sectional study the relation between stage of HIV disease and age, sex, needle sharing, ethnicity, self-reported history of alcohol consumption and CAGE scores. IVDA from a single municipal hospital were subdivided into three groups according to HIV disease status. Group 1 comprised 42 individuals with AIDS; group 2 comprised 114 who were HIV positive but without AIDS; and group 3 comprised 52 who were HIV negative. Information on alcohol consumption and CAGE responses were obtained by questionnaire and interview. Discriminant analysis indicated that alcohol abuse, assessed either by self-reported consumption or by CAGE scores, was significantly more common in the AIDS group than in either the HIV positive or the HIV negative groups, when controlled for age, sex, and needle sharing status. The relative risk of AIDS was 3.8 times higher in the heavy drinkers than in moderate drinkers. Needle sharing was also more common in the AIDS group than in the HIV positive or HIV negative groups when the other factors were controlled for. AIDS was more common in black than white IVDA, and this increased frequency did not appear related to alcohol consumption since the distribution of heavy drinkers within each category of HIV disease did not differ within the ethnic groups. These data indicate that a history of heavy alcohol consumption is more common in IVDA with AIDS than in IVDA at earlier stages of HIV disease.

Effect of ribavirin and amantadine on early hepatitis C virus RNA rebound and clearance in serum during daily high-dose interferon.

The early rebound in serum HCV RNA during HCV dynamic studies with high-dose interferon may be due to de novo infection with interferon escape quasispecies. We simultaneously measured serum alanine aminotransferase (ALT) and HCV RNA at rapid intervals in chronic HCV liver disease patients during interferon therapy alone or in combination with ribavirin and amantadine. HCV RNA declined rapidly between 0 and 48 hr in all patients (phase 1). Ribavirin and amantadine significantly increased this phase 1 decline. In all four monotherapy patients with viral rebound, the increasing levels of HCV RNA were associated with a parallel increase in serum ALT, consistent with a hepatitis flare or de novo infection. By contrast, in the four monotherapy patients without viral rebound, and all eight patients receiving combination therapy, the slow progressive phase two decay was associated with declining serum ALT levels. Ribavirin or ribavirin and amantadine significantly and incrementally increased the phase two HCV RNA clearance. Dynamic sequencing in the HVR1 region in one rebound patient confirmed the potential for rapid evolutionary changes during interferon therapy. These preliminary data suggest that early viral rebound might be associated with de novo infection with interferon escape HCV variants, which in turn are attenuated by ribavirin and amantadine.

Digital Image Analysis of the Distribution of Proliferating Cell Nuclear Antigen in Hepatitis C Virus-Related Chronic Hepatitis, Cirrhosis, and Hepatocellular Carcinoma

Viral dynamic studies in chronic hepatitis C virus (HCV) infection indicate a significantly shortened survival of virus-infected cells. Since at the steady state of chronic viral infection, the rate of infected cell elimination equals new cell regeneration, this would imply a high rate of hepatocyte turnover in chronic HCV liver disease. We estimated the fraction of regenerating hepatocytes in liver biopsy sections in chronic HCV liver disease, cirrhosis, and hepatocellular carcinoma (HCC). We used antibodies to proliferating cell nuclear antigen (PCNA) to detect proliferating cell nuclei in liver biopsy specimen from controls and patients with chronic hepatitis, cirrhosis, and HCC. We also used bis-benzimide to label fluorescently all hepatocyte nuclei simultaneously. Using digital image analysis, we calculated the area occupied by PCNA-stained hepatocyte nuclei, as a fraction of the total area occupied by fluorescently labeled hepatocyte nuclei (labeling index; LI). Antibody staining was negligible in the control specimen. The mean ± SE PCNA LI increased from 0.21 ± 0.1 in chronic hepatitis to 0.63 ± 0.15 in HCC. There was no significant difference between chronic hepatitis and cirrhosis. The fraction of cells undergoing regeneration is increased in chronic HCV liver disease, HCV-related cirrhosis, and HCC. Increased hepatocyte turnover could provide the link between chronic HCV liver disease and HCC.

Differential Effects of Nucleoside Analogs on Oxidative Phosphorylation in Human Pancreatic Cells

Although nucleoside analogs as a group inhibit mtDNA replication, individually they target specific organs for toxicity. For example, dideoxyinosine(ddI) is most closely associated with clinical pancreatitis and dideoxycytosine (ddC) with peripheral neuropathy. Comparison of the differential effects of these analogs on mitochondrial function in relevant human cell lines could provide general clues as to the mechanisms of their differential toxicity. We compared the effects of ddI [and its intracellular metabolite dideoxyadenosine (ddA)], with other nucleoside analogs ddC, Azidothymidine (AZT) and didehydrodeoxythymidine(d4T) on mtDNA elongation, cytotoxicity, oxidative phosphorylation, and cellular ATP concentration in a human pancreatic cell line, Capan-1 cells. AZT, like all the other analogs tested, altered mtDNA elongation, but had no other effect on these cells. Both ddC and d4T, but not ddI (20 μm and 50 μM), reduced total dish protein (a measure of cell numbers) in cells grown to confluence. The effect of ddA was intermediate. All (except AZT) increased lactate concentration in the cell culture medium. Dideoxycytosine (ddC) and d4T did not significantly affect cell oxygen consumption, expressed as a fraction of total dish protein. By contrast, ddI and ddA reduced basal and/or FCCP-stimulated oxygen consumption. %Dideoxycytosine (ddC) but not ddI or ddA (50 μM) was cytotoxic to cells after six days of growth. Nevertheless, the ATP content (expressed as a fraction of surviving cells) for ddC-, ddI-, and ddA-treated cells was similar to control cells. Cytotoxicity was apparent for ddI, ddA, as well as ddC after seven days. Paradoxically, cell ATP content was now significantly higher than control cells. Electron microscopy of cells treated with ddI confirmed significant ultrastructural changes affecting the inner mitochondria membrane and cristae. In conclusion, these data suggest that nucleoside analogs uniformly induce damage to mtDNA. However, the mitochondrial phenotypic damage induced by ddI and ddA appear to result in less Capan-1 cytotoxicity than ddC and d4T. The link between these differential effects and ddI pancreatitis is unclear.

Cytomegalovirus colitis in patients with acquired immunodeficiency syndrome.

The spectrum of presentation of complications in patients with human immunodeficiency virus (HIV) disease is changing, in line with their improved survival. Infection of the colon with cytomegalovirus (CMV) is now more commonly encountered in clinical practice. We have reviewed the medical records of eleven patients with clinical and pathological evidence of CMV colitis. The clinical presentation, endoscopic and histological findings, and simultaneous infection of other organs with CMV are discussed. Diarrhoea in association with abdominal pain is the most frequent symptom complex in these patients and should raise the clinical index of suspicion for CMV colitis.