Plasma leptin concentration increases early during highly active antiretroviral therapy for acquired immunodeficiency syndrome, independent of body weight.

Leptin, the protein product of the obese gene (ob), is secreted by adipocytes. Circulating leptin levels correlate with fat mass in humans, including individuals infected with HIV. Leptin serves as an adipostatic hormone, a permissive factor for reproduction and a modulator of immune function. Leptin is a cytokine, and has been demonstrated to enhance CD4 cell proliferation and IL-2 secretion from CD4 cells in vitro. The role of leptin in HIV-positive patients treated with highly active antiretroviral therapy (HAART) has not been well defined. We haveevaluated leptin levels in HIV-infected individualsduringthe early phase of HAART. We measured plasma leptin levels in 15 antiretroviral-naive HIV positive patients at baseline and after 1 and 4 weeks of HAART. After the first week of therapy, mean leptin level and CD4 count were increased compared to baseline, 6.0 vs 7.2 ng/ml (p = 0.004) and 377 vs 432 cells/ul (p = 0.014), respectively. In contrast, mean body mass index (BMI) remained unchanged 27.0 vs 26.8 kg/m2 (p < 0.08). After four weeks of therapy, leptin and BMI values were unchanged compared to baseline, 6.0 vs 5.9 (p < 0.4) and 27.0 vs 26.9 (p < 0.5), respectively, whereas CD4 count continued to increase to 491 cells/ul (p < 0.012 compared to baseline). These data demonstrate an early transient increase in plasma leptin levels in HIV positive patients initiated on HAART, despite a lack of change in BMI. It is unclear if the transient increase in leptin is related to its role as a cytokine, a metabolic regulator, or reproductive factor.

Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature.

BACKGROUND: A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. METHODS: We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. RESULTS: At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. CONCLUSIONS: Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

The effect of statins on mortality in patients with bacteremia.

The statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, act to regulate the biosynthesis of cholesterol. Statins also deplete nonsterol cholesterol precursors, the isoprenoids, which are necessary for prenylation of critical membrane proteins that regulate cellular communication, including the inflammatory response. In a retrospective review of 388 bacteremic infections due to aerobic gram-negative bacilli and Staphylococcus aureus, there was a significant reduction in both overall (6% vs. 28%; P=.002) and attributable (3% vs. 20%; P=.010) mortality among patients taking statins compared with patients not taking statins. This reduction in mortality persisted in a multivariate analysis (odds ratio, 7.6; 95% confidence interval, 1.01-57.5). Among the statin group, diabetes, hypertension, and coronary artery disease were more prevalent (P<.001), and there were more skin and soft tissue infections identified as sources of bacteremia (P=.008). These data suggest a potential clinical role of statins in bacteremic infection; however, the mechanism by which mortality is reduced remains undefined.

Alterations in serum levels of lipids and lipoproteins with indinavir therapy for human immunodeficiency virus-infected patients.

Alterations in lipid metabolism have been associated with the use of protease inhibitors. Sequential lipid analyses were performed on serum samples from human immunodeficiency virus-infected antiretroviral-naive patients who received indinavir in combination with two nucleoside reverse transcriptase inhibitors. Serum levels of cholesterol, triglycerides, high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) were measured at baseline and at periodic intervals. After 48 weeks of indinavir therapy, mean serum levels +/- SD rose as follows: cholesterol, from 167.2 +/- 36.0 to 206.3 +/- 32.4 mg/dL (P < .0005); triglycerides, from 110.4 +/- 47.5 to 158.4 +/- 72.5 mg/dL (P < .0101); and LDLs, from 106.6 +/- 35.1 to 136.1 +/- 31.6 mg/dL (P = .0029). There was no significant change in the serum HDL fraction. Mean serum lipoprotein (a) levels +/- SD rose from 6.5 +/- 1.4 to 9.6 +/- 2.0 mg/dL after 30 weeks (P = .0695). Potential mechanisms for the noted increases include alterations in serum lipoprotein lipase activity or changes in hepatic lipid metabolism. The clinical significance of these changes remains to be determined.

Serum calcitonin precursors in sepsis and systemic inflammation.

High serum levels of the calcitonin (CT) prohormone, procalcitonin (pro-CT), and its component peptides occur in systemic inflammation and sepsis. Using two different assays, we undertook a prospective study to determine the utility of serum precalcitonin peptides (pre-CT) as markers in this condition. Twenty-nine patients meeting criteria for the systemic inflammatory response syndrome were studied daily in two intensive care units. Sera were collected, and APACHE II scores were determined until recovery or death. All patients had markedly elevated serum pre-CT. Prognostically, peak values were the most important. The highest values portended mortality, and a lower level could be ascertained below which all patients survived. Peak pre-CT levels were significantly higher in patients with infection documented by blood cultures than in those patients with no documented infection from any source (P < 0.05). Mature CT remained normal or only moderately elevated. Compared with the serum pre-CT levels, receiver operating characteristic curve analysis revealed that the APACHE II scores, although more cumbersome, were better overall predictors of mortality. Thus, pre-CT is an important serum marker for systemic inflammatory response syndrome and is predictive of outcome. It also provides data concerning the presence of severe infection and may prove to be clinically useful for proactive patient care.

Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS.

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Mycobacterium kansasii bacteremia in patients infected with human immunodeficiency virus.

In a retrospective review of microbiology records at the George Washington University Hospital from 1980 through 1990, Mycobacterium kansasii bacteremia was identified in 10 patients; this finding represented 4.5% of nontuberculous mycobacterial blood cultures. M. kansasii was isolated from respiratory specimens from all 10 patients, and pulmonary parenchymal changes were noted in five patients. The median survival time was 14 weeks; however, only five patients received therapy with two or more drugs active against M. kansasii.

Wasting syndrome in AIDS: pathophysiologic mechanisms and therapeutic approaches.

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever and diarrhea. The pathophysiologic mechanisms responsible for this syndrome are not well defined, but it is clear that this is a multifactorial process in which the relative contribution of individual etiologic factors vary among patients. Considerations include inadequate diet, malabsorptive phenomena, metabolic derangements, and cytokine activity. The onset of opportunistic infections is often accompanied by a hypermetabolic state characterized by progressive weight loss. Potential cytokines that may promote weight loss in AIDS patients include tumor necrosis factor, interleukin-1, interleukin-6, and alpha-interferon. At present there is no effective treatment. Multiple therapeutic methods, including enteral and parenteral alimentation, appetite stimulants, recombinant growth hormone, and cytokine modulators, are currently being explored.

Fascioliasis: case reports and review.

Fasciola hepatica, a zoonotic liver fluke, can cause disease in humans. Fascioliasis, while common in some tropical and developing countries, is uncommon in the United States. We report two cases of fascioliasis that illustrate both the hepatic and biliary stages of the disease. Clinical features and diagnostic aspects including serologic, radiographic, and histopathologic studies are emphasized. Praziquantel was ineffective in treatment of both patients. Bithionol appears to be an effective treatment for fascioliasis.

Ganciclovir treatment of cytomegalovirus ventriculitis in a patient infected with human immunodeficiency virus.

Histopathologic evidence of central nervous system involvement with cytomegalovirus (CMV) has been well recognized in patients infected with human immunodeficiency virus (HIV). However, clinically symptomatic disease has been decidedly less common. In this report, we describe a patient infected with HIV who developed an acute change in neurological status. Gadolinium-enhanced magnetic resonance imaging and analysis of cerebrospinal fluid revealed CMV ventriculitis and meningoencephalitis. Treatment with ganciclovir resulted in radiological improvement of the ventriculitis and negative CMV cultures but little clinical neurological improvement.

Listeria monocytogenes infections in patients with AIDS: report of five cases and review.

Five patients with AIDS and Listeria monocytogenes infection (three cases of bacteremia and two of meningitis) are reviewed. Four patients had prior or concurrent gastrointestinal illness. Two patients received corticosteroids. A 7- to 21-day course of ampicillin was administered with or without a 7- to 14-day course of gentamicin. This regimen was effective, with no evidence of relapse 7-8 months after therapy was discontinued. The relative infrequency of infection with L. monocytogenes in AIDS patients is unexpected. Tumor necrosis factor (TNF) appears to be essential in the inhibition of Listeria in vivo. Elevated levels of TNF in AIDS patients may be protective against listeriosis and thus help explain the low prevalence of listerial infection in this population. Nonetheless, although L. monocytogenes is an uncommon cause of illness in patients infected with the human immunodeficiency virus, it cannot be dismissed as a cause of undefined meningitis or sepsis.

Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta.

Monocytes in the circulation of normal individuals express two receptors for the constant region of immunoglobulin, Fc gamma RI and Fc gamma RII. In contrast, we have observed that AIDS monocytes express significant levels of a third Fc gamma R, Fc gamma RIII (CD16), which is normally associated with activation or maturation of the monocyte population. By dual-fluorescence analysis using a monoclonal antibody specific for Fc gamma RIII (MAb 3G8), 38.5 +/- 3.2% of the LeuM3 (CD14)-positive monocytes in AIDS patients were CD16 positive as compared to 10.4 +/- 1.0% for healthy individuals (n = 29; P less than 0.005). Furthermore, AIDS monocytes expressed Fc gamma RIII-specific mRNA which is expressed minimally or not at all in control monocytes. As a recently identified inducer of Fc gamma RIII expression on blood monocytes, transforming growth factor-beta (TGF-beta) was found to be elevated in the serum and/or plasma of AIDS patients. Moreover, incubation of normal monocytes with AIDS serum or plasma induced CD16 expression which correlated with serum TGF-beta levels (r = 0.74, P less than 0.001) and was inhibited with a neutralizing antibody to TGF-beta. Thus, the increased CD16 expression on peripheral blood monocytes in AIDS patients may be the consequence of elevated circulating levels of the polypeptide hormone TGF-beta.

Flavimonas oryzihabitans (Pseudomonas oryzihabitans; CDC group Ve-2) bacteremia in the immunocompromised host.

Flavimonas oryzihabitans, known previously as Pseudomonas oryzihabitans, and a member of the Centers for Disease Control group Ve-2, is a gram-negative organism that has rarely been implicated as a human pathogen. Flavimonas oryzihabitans appears to be a soil and saprophytic organism that survives in moist environments and is indigenous to rice paddles. To our knowledge, only seven cases of human infection caused by this organism have been reported; they involved four patients with bacteremia and three patients with peritonitis who were receiving continuous ambulatory peritoneal dialysis. In this report, we describe three immunocompromised patients with catheter-associated bacteremia: a patient with cancer, a patient with acquired immunodeficiency syndrome, and a patient with sickle cell disease. There is emerging clinical evidence that F oryzihabitans should be recognized as an organism that is capable of causing human disease, particularly in immunocompromised patients and with the increased usage of permanent catheters.

Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine.

Dideoxycytidine (ddC) and dideoxyinosine (ddI) are nucleoside derivatives that exhibit antiretroviral activity against the human immunodeficiency virus (HIV). Both of these agents are under active investigation as potential therapies for patients with HIV infection. In addition, both drugs may be obtained for HIV-infected individuals who cannot tolerate zidovudine. A major focus of the research effort involving these agents has been to define their toxicities. Both agents may cause peripheral neuropathy. We wish to report a patient who developed severe neuropathy following the administration of ddI that was given shortly after the patient was removed from a clinical trial of ddI. The rapid development of toxicity indicates that this side effect is additive or synergistic for these agents.

Peripheral blood mononuclear cell interleukin-2 and interferon-gamma production, cytotoxicity, and antigen-stimulated blastogenesis during experimental rhinovirus infection.

To determine whether rhinovirus infection induced a systemic cellular immune response in humans, specific antigen-stimulated blastogenesis, natural killer cell activity, and mitogen-stimulated production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells (PBMC) were quantified during experimental rhinovirus infection of normal volunteers. Phytohemagglutinin-stimulated interleukin-2 production by PBMC collected on day 5 after rhinovirus inoculation was increased fourfold compared with production by PBMC collected before rhinovirus challenge (P less than .05); phytohemagglutinin-stimulated interferon-gamma production was doubled (P less than .05). An inverse relationship was observed between the increase in interleukin-2 production and both nasal mucus production (P less than .02) and the number of days virus was cultured from nasal washings (P less than .02). Natural killer cell-mediated cytotoxicity of PBMC collected on day 5 after rhinovirus challenge was also increased (P less than .01) compared with preinfection levels, as was specific antigen-stimulated blastogenesis on day 21 (P less than .05). The extent of blastogenic response correlated directly with both mucus production (P less than .05) and the number of days virus was cultured from nasal washings (P less than .05). These observations are consistent with the hypothesis that rhinovirus infection results in activation of a systemic cellular immune response.

Clinical, virologic, and immunologic effects of combination therapy with ribavirin and isoprinosine in HIV-infected homosexual men.

We evaluated the clinical, immunologic, and virologic effects of oral treatment with ribavirin and isoprinosine for up to 3 months in asymptomatic, HIV-culture-positive homosexual men. Fifteen consecutive men received isoprinosine 4 g/day (1 g q.i.d.), and 800 (9 men) or 1,200 mg/day (6 men) of ribavirin. Five men in each ribavirin dosage group completed at least 2 months of treatment. No unexpected toxicities were observed. Eight minor HIV-related events occurred in six men while on study. All men remained HIV-positive, and time to positive culture decreased by at least 4 days in three men from each treatment group. Serum p24 levels did not change in two men who were p24 antigenemic and received 800 mg/day of ribavirin. Treatment was associated with a generalized lymphopenia affecting all lymphocyte subsets including CD4, which was partially reversible 1 month after stopping treatment. Most of the men remained anergic on DTHS skin testing. No improvements were noted in in vitro lymphoproliferative responses to antigens or in NK cell activity (which decreased significantly in the 1,200 mg/day ribavirin group). Although well tolerated at the doses employed, the combination of ribavirin and isoprinosine produced an unexpected generalized lymphopenia and did not exhibit HIV-suppressive or immunorestorative effects.