Lymphoepithelioma-like gastric carcinoma: an unusual consequence of Epstein-Barr virus infection in an HIV-infected woman.

Lymphoepithelioma-like-gastric carcinoma (LEL-GC) is an Epstein-Barr virus (EBV)-associated neoplasm of the stomach reported to have a better prognosis than conventional gastric adenocarcinoma. Unlike other EBV-associated malignancies, particularly lymphoproliferative disorders and undifferentiated nasopharyngeal carcinoma, for which risk has been shown to increase in human immunodeficiency virus (HIV) infection, LEL-GC remains rare; only one HIV-infected patient with LEL-GC has been reported previously. We describe an aggressive case of EBV-associated LEL-GC in a woman co-infected with HIV 1 and hepatitis C virus. In situ hybridization of an endoscopic biopsy specimen for EBV-encoded small RNA confirmed the presence of this agent exclusively in the gastric cancer cells. Our patient had recently started antiretroviral therapy, suggesting that immune reconstitution may have been a factor in presentation of this tumour.

Clinical characteristics of bacteraemia caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type ß-lactamases.

Clin Microbiol Infect 2012; 18: 887-893 ABSTRACT: A multicentre, case-control study was conducted to assess risk factors and patient outcomes of bacteraemia caused by Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). One hundred and five and 20 patients with bacteraemia caused by ESBL-producing and KPC-producing organisms were matched to controls who had bacteraemia caused by non-ESBL/KPC-producing organisms, respectively. Independent risk factors for ESBL production included admission from a nursing home (OR 4.64; 95% CI 2.64-8.16), chronic renal failure (OR 2.09; 95% CI 1.11-3.92), the presence of a gastrostomy tube (OR 3.36; 95% CI 1.38-8.18), length of hospital stay before infection (OR 1.02; 95% CI 1.01-1.03), transplant receipt (OR 2.48; 95% CI 1.24-4.95), and receipt of antibiotics with Gram-negative activity in the preceding 30 days (OR 1.76; 95% CI 1.00-3.08). Twenty-eight-day crude mortality rates for patients infected with ESBL-producing or KPC-producing organisms and controls were 29.1% (34/117) and 19.5% (53/272), respectively (OR 1.70; 95% CI 1.04-2.80). On multivariate analysis, inadequate empirical therapy (OR 2.26; 95% CI 1.18-4.34), onset of bacteraemia while in the intensive-care unit (OR 2.74; 95% CI 1.47-5.11), Apache II score (OR 1.17; 95% CI 1.12-1.23) and malignancy (OR 2.66; 95% CI 1.31-5.41) were independent risk factors for mortality. CTX-M was the most common ESBL type in Escherichia coli, whereas SHV predominated in Klebsiella spp. and Enterobacter spp.

Successful treatment of Old World cutaneous leishmaniasis caused by Leishmania infantum with posaconazole.

Old World cutaneous leishmaniasis is a widespread and potentially disfiguring protozoal infection that is endemic in the Mediterranean basin, Africa, and parts of Asia. Human infection is caused by several species of Leishmania parasites, such as Leishmania infantum. Available systemic and topical treatments vary in efficacy and are often unjustified due to their toxicity. We report on a case that was treated with posaconazole, a drug typically considered an antifungal agent but which also targets specific metabolic pathways of the parasite.

A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS.

Reverse transcriptase has been detected in the serum of HIV-negative patients with amyotrophic lateral sclerosis (ALS). An ALS-like disorder in HIV-positive patients can remit with antiretroviral therapy. Using the product enhanced assay technique, we measured reverse transcriptase activity in the serum and CSF of 23 HIV-negative patients with ALS and 21 neurologic disease controls. Results for CSF were not significant, whereas reverse transcriptase was detected in 56% of ALS sera vs 19% of controls.

Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection (AIDS Clinical Trials Group Protocol 360).

We undertook a prospective study to analyze cytomegalovirus (CMV) end-organ disease (EOD) in subjects with advanced human immunodeficiency virus (HIV) infection. Of 403 individuals without prior CMV EOD who were followed up for a median of 151 weeks, 56 died and 21 developed CMV EOD. Twenty of the subjects with CMV EOD had CD4 cell counts of < or =50 cells/mm3 and HIV RNA level of >10,000 copies/mL of plasma at baseline; in these 20 subjects, an increase of CMV DNA level to greater than the quantification limits was associated with CMV EOD. A CD4 cell count of < or =100 cells/mm3 and an HIV RNA level of >10,000 copies/mL of plasma at baseline, a CMV DNA level of >200 copies/mL of blood during follow-up, or development of CMV EOD were all associated with decreased survival. HIV-infected subjects with CD4 cell counts of < or =50 cells/mm3 and HIV RNA levels of >10,000 copies/mL of plasma should have blood fractions screened for CMV DNA; if CMV DNA is detected, CMV prophylaxis might be considered.

HIV/Hepatitis B and C co-infection: pathogenic interactions, natural history and therapy.

Recent advances in antiretroviral therapy for HIV infection have substantially improved overall mortality, as well as morbidity from life-threatening opportunistic infections. In place of the usual HIV-associated opportunistic infections, morbidity and mortality due to the sequelae of hepatitis B (HBV) and C virus (HCV) infections have taken on a leading role in HIV-infected individuals. This review will examine the pathogenesis of these viruses in the setting of co-infection and the effect of immunosuppression with HIV, the natural history of co-infection, with particular attention to the effect on serological and histological markers, and the effect of immune reconstitution on the course of HBV and HCV infection. Consideration will also be given to the effect of HIV infection on HBV and HCV load (especially for HCV) and progression of liver disease. Finally, we will discuss the rapidly evolving area of therapy, with particular attention to many of the newer agents now in clinical trials, as well as combinations of these agents.

Cytomegalovirus ventriculoencephalitis in a bone marrow transplant recipient receiving antiviral maintenance: clinical and molecular evidence of drug resistance.

We describe a case of CMV ventriculoencephalitis in a severely immunocompromised bone marrow transplant recipient who was receiving combination therapy with ganciclovir and foscarnet for treatment of viremia and retinitis. Analysis of sequential viral isolates recovered from the patient's cerebrospinal fluid suggested that disease developed because of the presence of viral resistance and, possibly, low tissue penetration of antiviral agents.

HIV-associated wasting in the HAART era: guidelines for assessment, diagnosis, and treatment.

Wasting (malnutrition) and lipodystrophy are the two major nutritional alterations in human immunodeficiency virus (HIV)-infected individuals. Both wasting and lipodystrophy may involve a decrease in body fat content, while wasting-but not lipodystrophy-also includes the loss of lean body mass. Lipodystrophy has made the identification of wasting increasingly more difficult. The diagnosis of wasting depends on a definition of the condition that takes into account sex and cultural differences, as well as measurements of body cell mass. Patient management involves a concurrent, comprehensive approach designed to restore lost body cell mass and weight. The authors make recommendations for defining, diagnosing, and treating HIV-associated wasting. Specific therapies include testosterone replacement, other anabolic steroids, and recombinant human growth hormone. Other adjunctive measures, such as progressive resistance exercise and cytokine modulation, may also be utilized. Expected outcomes from effective treatment include restored body cell mass, improvement in quality of life, and reduced rates of hospitalization. Future directions for research should address the need for optimal treatment strategies.

Detection and quantitation of human immunodeficiency virus type 1 in the female genital tract. The Division of AIDS Treatment Research Initiative 009 Study Group.

Human immunodeficiency virus type 1 (HIV-1) was detected in the genital tracts of 59% of 225 women by RNA PCR and in 7% of the women by culture. In a comparison of two sampling methods, endocervical swabs were more sensitive than cervicovaginal lavage for HIV-1 RNA detection by PCR but not by culture and their sensitivity was independent of the concentration of HIV-1 RNA.

Viability and functional activity of cryopreserved mononuclear cells.

Factors that influence viability and function of cryopreserved peripheral blood mononuclear cells (PBMC) were identified on 54 samples from 27 AIDS Clinical Trial Units. PBMC viability ranged from 1 to 96% with a median of 70%, was higher in laboratories with experienced staff, and was not significantly associated with CD4 cell number. Function of cryopreserved PBMC, measured by lymphocyte proliferation, was associated with viability. Preparations with viability greater than or equal to 70% had consistent proliferative responses and were suitable for functional analyses.

Treatment guidelines for HIV-associated wasting.

Patients with acquired immunodeficiency syndrome (AIDS) often suffer from weight loss manifested by a loss of body cell mass (BCM). The causes of human immunodeficiency virus (HIV)-associated wasting may include anorexia, malabsorption, and a variety of altered metabolic states. Malabsorption and diarrhea may result from gastrointestinal tract opportunistic infections or from direct effects of HIV on the gastrointestinal tract. Infection with HIV may produce metabolic derangements that alter nutrient utilization, resulting in loss of BCM. Nutritional assessment of the patient with AIDS should include an evaluation of BCM and physical and psychosocial functioning. Antiretroviral therapy and eradication of opportunistic infections do not always reverse wasting. Treatment should include nutritional counseling. Total parenteral nutrition is sometimes of benefit, particularly in patients with damaged gastrointestinal tracts. Dronabinol and megestrol acetate may promote weight gain; however, dronabinol may have adverse effects, and most of the gain with megestrol acetate is in fat rather than BCM. If gonadal dysfunction is present, testosterone replacement therapy should be included in the treatment plan. Some studies suggest that oral anabolic steroids may improve muscle strength and body composition. In randomized, placebo-controlled trials, mammalian-derived human growth hormone (rhGH[m]) has produced sustained weight and BCM gains in AIDS patients. If a patient continues to lose BCM after the above factors have been addressed and corrected, a 12-week course of rhGH[m] is indicated. Halting the progression of HIV-associated wasting may improve survival, enhance physical and social functioning, and enrich quality of life.

Oropharyngeal candidiasis: a review of its clinical spectrum and current therapies.

With the increased use of antibiotics and immunosuppressive agents, oropharyngeal candidiasis is becoming more common. This infection is also associated with such advances in medical management as chemotherapy and organ transplantation and with human immunodeficiency virus infection. Various topical and systemic agents are available to treat patients with candidiasis, but optimal management can be elusive. Treatment of uncomplicated oropharyngeal candidiasis in the immunocompetent patient involves selecting a particular formulation of a topical medication based on oral conditions, length of contact time, and taste, texture, and cost of the medication. Treatment of severe oropharyngeal candidiasis, particularly in patients with a compromised immune system, is often more difficult, and relapses are common. Reports of resistance to systemic agents, particularly in patients needing recurrent therapy, are increasing. Amphotericin B, long used as an intravenous agent, is now available as an oral suspension that may offer therapeutic benefits comparable to those of systemic therapy without the toxicity associated with systemic absorption.

Treatment of HIV infection and its complications.

Because the AIDS epidemic continues to grow, there is a sense of urgency to develop new treatment strategies, both for HIV infection and for AIDS-related illnesses. The rapid gathering of basic information related to HIV type 1 biology and opportunistic infections has led to an explosion in physicians' ability to diagnose, prevent, and treat HIV disease and its associated complications. Research in this rapidly evolving field is likely to lead to further advances in the months and years that follow.

Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains.

Reference strains of HIV-1 from the NIH AIDS Research and Reference Reagent Program, including wild-type IIIB, G762-3, and AZT resistant with RT 215T-->Y (G910-11/AZT); 67D-->N, 70K-->R, 215T-->F, 219K-->Q (G691-2/AZT); as well as nevirapine (NEV) resistant with 181Y-->C (N119/NEV); and 103K-->N, 181Y-->C (A17/NEV), were subjected to quantitative parametric efficacy analysis using AZT, stavudine (D4T), and nevirapine (NEV) singly or in combinations in MT4 or MT2 cells. The median-effect principle and combination index (CI) method of Chou-Talalay (see Ref. 26) have been used, which take into account both the potency (Dm value or EC50) and the shape of the dose-effect curve (m value). Under standardized assay conditions, G910-11 and G691-2 strains showed 600- and 7800-fold resistance to AZT, and N119 and A17 strains showed 3600- and 1000-fold resistance to NEV at the EC50 level, respectively. AZT-resistant strains exhibited slight cross-resistance to D4T. Computerized analysis indicates that IIIB gave sigmoidal dose-effect curves (m = 2.8, 3.4, and 3.1 for AZT, D4T, and NEV, respectively) whereas drug-resistant strains showed negative sigmoidicity toward the corresponding AZT or NEV, with m = 0.27-0.73. Therefore, the degrees of drug resistance are drastically different at classic EC50 and at therapeutically more relevant EC95 levels (ranging from severalfold to several log orders). Combinations of AZT+NEV and AZT+NEV+D4T showed synergism against IIIB, G762-3 (wild type) and A17/NEV, G910-11/AZT strains. D4T+NEV and AZT+D4T showed nearly additive or moderate antagonism. Synergism or additive effect leads to a favorable dose-reduction index (DRI). The present study on RT inhibitors provides quantitative assessment of the combinations of AZT, NEV, and D4T against HIV infections involving drug-sensitive and drug-resistant HIVs.

Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz.

Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication in vitro (ED50 approximately 10 microM), undergoes extensive metabolism in vivo. Most of the orally administered drug undergoes opening of the dithiolethione ring, reduction, recyclization, and methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine ("metabolite III"). We report here that metabolite III inhibits viral replication in vitro (ED50 approximately 25 microM) in acutely infected H9 and CEM T cell lymphoma cell lines. Although both metabolite III and oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in the chronically infected U1 promonocytic leukemia cell line, only metabolite III was able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2 cells suggest that oltipraz inhibits an early stage of the viral life cycle, whereas metabolite III affects human immunodeficiency virus type 1 replication at a step distal to viral integration. This is consistent with the finding that oltipraz inhibits reverse transcriptase, whereas metabolite III does not. Although the mean ED50 for metabolite III in acutely infected peripheral blood mononuclear cells was 18 microM, the ED50 was below 5 microM in three of eight independent experiments. Studies of metabolite III in combination with oltipraz in acutely infected peripheral blood mononuclear cells demonstrated significant antiviral synergy. These results raise the possibility that the in vitro potency of oltipraz may underestimate its antiretroviral activity in vivo. Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia.

Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis.

INTRODUCTION: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy. METHODS: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods. RESULTS: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different. CONCLUSION: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

Oltipraz, a novel inhibitor of human immunodeficiency virus type 1 (HIV-1) replication.

Glutathione (GSH) levels are markedly depleted in patients infected with human immunodeficiency virus type 1 (HIV-1) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiols prevents HIV-1 replication in cultured cells. We were intrigued whether chemopreventive enzyme inducers might represent a more pharmacologically feasible method to inhibit HIV-1 replication since these compounds elevate intracellular concentrations of GSH at nontoxic doses in vivo. After establishing that all inducers surveyed were able to elevate GSH levels in human T-cell and monocytoid cell lines, we were surprised to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM). Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhibit acute HIV-1 replication by inactivating reverse transcriptase (RT). However, among DTTs that inhibit HIV-1 replication in acutely infected cells, only oltipraz was able to inhibit HIV-1 replication in a chronic infection model. Thus, in addition to inactivating RT, oltipraz appears to have an additional antiviral mechanism distal to viral integration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-1 replication in chronically infected cells; we are also attempting to determine the bioorganic mechanism for the inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectively, our studies should be relevant to understanding the diverse medicinal properties of DTTs. Oltipraz, an antischistosomal drug undergoing clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to consider oltipraz as a therapeutic agent not only for its antiretroviral activity, but also for the prevention of HIV-1 associated neoplasms.