Edward A. Lew

Liver biopsy findings in 501 patients infected with human immunodeficiency virus (HIV)

Patients infected with human immunodeficiency virus (HIV) are at risk for a variety of liver diseases. We undertook a retrospective study of 501 HIV-seropositive patients to assess the yield of percutaneous liver biopsy. The most common indications for liver biopsy were liver test abnormalities (89.5%), fever for 2 weeks (71.9%), and hepatomegaly (52.0%). The most common biopsy-derived diagnosis was Mycobacterium avium complex (MAC), seen in 87 (17.4%) biopsies. Mycobacterium tuberculosis was found in 13 biopsies (2.6%). In 28 biopsies (5.6%) mycobacteria was seen, but speciation of the organism was not possible. Chronic active viral hepatitis was seen in 60 biopsies (12.0%). Opportunistic hepatic infection from other organisms was found in 14 biopsies (2.8%). The most common neoplasm was lymphoma, which was seen in 12 biopsies (2.4%). MAC infection of the liver was associated with elevated alkaline phosphatase (p = 0.01). Among patients with fever for 2 weeks after an extensive negative workup including bone marrow biopsy, 58.2% had a diagnosis by liver biopsy. Overall, 64.3% of liver biopsies yielded a histopathological diagnosis, 45.7% of which were potentially treatable. We could not evaluate whether liver biopsy had a positive effect on patient outcome and survival, nor did we attempt to prove that liver biopsy resulted in a change in treatment or a change in preprocedure clinical diagnosis. Thus, questions about the efficacy of liver biopsy cannot be answered. Liver biopsy may be a helpful diagnostic tool in HIV-positive patients with fever, liver test abnormalities or hepatomegaly.

CCR5 and CXCR4 expression on memory and naive T cells in HIV-1 infection and response to highly active antiretroviral therapy

Objective: To measure CCR5 and CXCR4 chemokine receptor expression on CD4 and CD8 T cells in HIV‐1 infection and to relate levels to the distribution of CD45RO memory and CD45RA‐naive subsets, measures of disease activity, and response to highly active antiretroviral therapy (HAART). Design: Fourteen untreated HIV‐1‐infected patients, 18 patients at 3‐ to 4‐weeks after beginning HAART, and 35 uninfected control subjects were studied. Methods: Four‐color cytofluorometry with appropriate conjugated monoclonal antibodies (mAbs) was performed to define CD45RA and CD45RO subsets of CD4 and CD8 T cells and measure their expression of CCR5, CXCR4, and CD38. Results: HIV‐1‐infected patients had higher CCR5 levels and lower CXCR4 levels on CD4 and CD8 T cells and their CD45RO/CD45RA subsets than control subjects did. However, CCR5 elevation was statistically significant only for CD4 T cells and their subsets, and CXCR4 depression was significant for CD8 T cells and their subsets (and for CD4:CD45RO cells). The elevation of CCR5 and depression of CXCR4 were not due to shifts in CD45RO/CD45RA subset proportions but to upregulation or downregulation within the subsets. CCR5 elevation on CD4 T cells was significantly restored toward normal by HAART, but the CXCR4 depression was not. CCR5 expression but not CXCR4 expression correlated with other measures of immunodeficiency (CD4 T‐cell levels), active infection (viral load), and cellular activation (CD38). Conclusions: CCR5 elevation is a concomitant of immune activation and viral replication that occurs in HIV‐1 infection, but the relation of CXCR4 depression to severity of infection, disease progression, and response to therapy remains undefined.

Oral and intravenous dosage forms of pantoprazole are equivalent in their ability to suppress gastric acid secretion in patients with gastroesophageal reflux disease

OBJECTIVE:The aim of this study was to assess the ability of pantoprazole to maintain gastric acid suppression in patients with gastroesophageal reflux disease who are switched from an oral (p.o.) to an intravenous (i.v.) dosage form.METHODS:A total of 65 patients with gastroesophageal reflux disease were administered either 40 or 20 mg of p.o. pantoprazole daily for 10 days, then were switched to either a matching dose of i.v. pantoprazole or to placebo for 7 days. Acid output (basal and maximal) was measured at the end of the p.o. treatment period and on the first and last days of i.v. therapy. In the primary efficacy analysis, the acid output values at the end of the p.o. pantoprazole treatment were compared with those at the end of the i.v. treatment. Safety was monitored by periodic vital sign measurements, clinical laboratory evaluations, ophthalmic examinations, electrocardiograms, and reports of adverse events. The data were tested by an analysis of covariance and by Wilcoxon signed rank and t tests.RESULTS:Maximal acid output (mean ± SD) in the 40 mg and 20 mg pantoprazole group after p.o. treatment was 6.5 ± 5.6 mEq/h and 14.5 ± 15.5 mEq/h, respectively; whereas, at the end of the i.v. treatment period, the values were 6.6 ± 6.3 mEq/h and 11.1 ± 10.2 mEq/h, respectively. In patients given i.v. placebo, acid output was significantly (p < 0.05) increased to 29.2 ± 13.0 mEq/h by day 7. Both p.o. and i.v. pantoprazole dosage forms had similar favorable safety and tolerability profiles.CONCLUSIONS:The p.o. and i.v. formulations of pantoprazole (40 and 20 mg) are equivalent in their ability to suppress gastric acid output. The i.v. form of pantoprazole offers an alternative for gastroesophageal reflux disease patients who are unable to take the p.o. formulation.

DIARRHEAL DISEASES ASSOCIATED WITH HIV INFECTION

Diarrhea is a major complication of HIV infection and adversely impacts health care costs, quality of life, and even survival of patients. There is a wide variety of potential causes of diarrhea in HIV-infected patients, and the number of pathogens found continues to increase with time. In addition, there is some controversy concerning the role of some organisms in the pathogenesis of diarrhea and the appropriate diagnostic evaluation of affected patients. This article reviews our current understanding of these pathogens and some of the diagnostic and therapeutic approaches for diarrhea associated with HIV infection.

Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

OBJECTIVES:In patients with Zollinger-Ellison syndrome (ZES) or other conditions requiring oral doses of proton pump inhibitors, it frequently becomes necessary to use parenterally administered gastric acid inhibitors. However, i.v. histamine-2 receptor antagonists are not effective at usual doses and lose their effectiveness because of tachyphlaxis. With the approval in the United States of i.v. pantoprazole, a substituted benzimidazole available in i.v. formulation, it will become possible to acutely manage gastric acid secretion in the acute care setting of a hospital. This study was developed to monitor the safety and establish the efficacy of i.v. pantoprazole as an alternative to oral proton pump inhibitors for the control of gastric acid hypersecretion in patients with ZES.METHODS:The efficacy of replacing oral PPI therapy with i.v. pantoprazole was evaluated in 14 ZES patients. After study enrollment, patients taking their current doses of oral PPI (omeprazole or lansoprazole) were switched to pantoprazole i.v. for 6 days during an 8-day inpatient period in the clinical research center. Effective control was defined as an acid output (AO) of <10 mEq/h (<5 mEq/h in patients with prior gastric acid-reducing surgery).RESULTS:The mean age of the 14 patients enrolled in the study was 52.4 yr (range = 38–67). Mean basal AO was 0.55 ± 0.32 mEq/h and mean fasting gastrin was 1089 pg/ml (range = 36–3720). Four patients were also diagnosed with the multiple endocrine neoplasia type I syndrome, nine were male, and two had previously undergone acid-reducing surgery. Before study enrollment, gastric acid hypersecretion was controlled in nine of 14 patients with omeprazole (20–200 mg daily) and five of 14 with lansoprazole (30–210 mg daily). In the oral phase of the study all patients had adequate control of gastric acid secretion, with a mean AO of 0.55 ± 0.32 mEq/h (mean ± SEM). Thereafter, 80 mg of i.v. pantoprazole was administered b.i.d. for 7 days by a brief (15 min) infusion and the dose was titrated upward to a predetermined maximum of 240 mg/24 h to control AO. A dose of 80 mg b.i.d. of i.v. pantoprazole controlled AO in 13 of 14 of the patients (93%) for the duration of the study (p > 0.05 compared to baseline values for all timepoints). One sporadic ZES patient (oral control value = 0.65 mEq/h on 100 mg of omeprazole b.i.d. p.o.) was not controlled with 80 mg of i.v. pantoprazole b.i.d. and dosage was titrated upward to 120 mg b.i.d. after day 2.CONCLUSIONS:There were no serious adverse events observed. Intravenous pantoprazole provides gastric acid secretory control that is equivalent to the acid suppression observed with oral proton pump inhibitors. Most ZES patients (93%) maintained effective control of AO previously established with oral PPIs when switched to 80 mg of i.v. pantoprazole b.i.d.; however, for difficult-to-control patients, doses >80 mg b.i.d. may be required.

DIAGNOSIS AND TREATMENT OF HEPATIC DISEASE IN PATIENTS WITH HIV

Liver involvement with opportunistic infections and neoplasms is a well-recognized component of AIDS, affecting most patients. The cause of hepatic disease in these patients may be divided into hepatitis, granulomatous disease, mass lesions, vascular lesions, hepatotoxic drugs, and nonspecific findings. With a rational approach, most patients with AIDS and liver disease can be diagnosed and treated in a cost-effective manner with low morbidity.

Intracellular cytokines in the acute response to highly active antiretroviral therapy

ObjectivesSuccessful highly active antiretroviral therapy (HAART) is usually associated with a rapid decline in HIV plasma RNA levels and a gradual increase in CD4 T cells. We examined whether changes in cytokine production and profile precede other immunological changes and whether these might occur in temporal association with plasma HIV RNA changes. Design and methodsEleven HIV-1-infected patients were enrolled into a prospective cohort study; eight patients were naive to antiretroviral therapy. Blood samples were collected pre-therapy (week 0) and at 1, 2, and 3 weeks post-initiation of therapy. ResultsAll 11 patients enrolled remained on triple HAART for 1 week, eight for 2 weeks, and six for ⩾ 3 weeks. When compared to week 0, these patients had a ⩾ 2-log10 decline in HIV plasma RNA levels and/or a decline to ⩽ 400 copies/ml by week 3 of therapy (p = 0.004). The numbers and percentages of CD4 and CD8 T cells, and the percentage of naive, memory, and activated T cells did not change significantly between weeks 0 and 1 or 0 and 3. Of all the immune parameters examined only: the percentage of CD4 T cells spontaneously producing tumor necrosis factor (TNF)-α (median, 2.4 versus 0.5% P = 0.025); the percentage of CD8 T cells spontaneously producing TNF-α (median, 0.6 versus 0.2% P = 0.037); and the percentage of CD3 T cells spontaneously producing interleukin-4 (median, 1.8 versus 0.8% P = 0.004) changed significantly between weeks 0 and 3. ConclusionsIn these patients, decreases in the percentage of T cells spontaneously producing TNF-α or interleukin-4 preceded changes in CD4 T cells. If confirmed by others, these observations may be useful as early predictors of response to and early failure of HAART.