A combination of electrochemistry and mass spectrometry to monitor the interaction of reactive species with supported lipid bilayers.

Reactive oxygen and nitrogen species (RONS), e.g. generated by cold physical plasma (CPP) or photodynamic therapy, interfere with redox signaling pathways of mammalian cells, inducing downstream consequences spanning from migratory impairment to apoptotic cell death. However, the more austere impact of RONS on cancer cells remains yet to be clarified. In the present study, a combination of electrochemistry and high-resolution mass spectrometry was developed to investigate the resilience of solid-supported lipid bilayers towards plasma-derived reactive species in dependence of their composition. A 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer was undisturbed by 200 µM H2O2 (control) but showed full permeability after CPP treatment and space-occupying oxidation products such as PoxnoPC, PAzePC, and POPC hydroperoxide were found. Electron paramagnetic resonance spectroscopy demonstrated the presence of hydroxyl radicals and superoxide anion/hydroperoxyl radicals during the treatment. In contrast, small amounts of the intramembrane antioxidant coenzyme Q10 protected the bilayer to 50% and LysoPC was the only POPC derivative found, confirming the membrane protective effect of Q10. Such, the lipid membrane composition including the presence of antioxidants determines the impact of pro-oxidant signals. Given the differences in membrane composition of cancer and healthy cells, this supports the application of cold physical plasma for cancer treatment. In addition, the developed model using the combination of electrochemistry and mass spectrometry could be a promising method to study the effect of reactive species or mixes thereof generated by chemical or physical sources.

[Gastroenterological function tests in the GP's office]. / Funktionstests für Magen und Darm sind auch beim Hausarzt einfach durchzuführen. Zu viel Säure, zu wenig Enzyme oder Fehlbesiedlung?

Breath tests are quick, noninvasive, simple to perform and reliable. In particular in patients with diarrhea, bloating, nausea and uncharacteristic abdominal symptoms, the H2 breath test is highly useful. Using this procedure, malabsorption of various different carbohydrates, the absorptive performance of the upper abdominal tract, the orocecal transit time, or bacterial overgrowth in the small bowel, can be determined. Using 24-hour pH-metry, the acidity in the stomach and esophagus can be measured, and reflux disease, for example, diagnosed. Today, elevated fat in the stool is detected on the basis of the beta carotene level in the serum. Further function tests for the detection of pancreatic insufficiency, such as the determination of fecal pancreatic elastase, are also available.

Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group.

PURPOSE: Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposi's sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS: We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposi's sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS: A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION: Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposi's sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.

[Diagnostics of the HIV infection]. / Die akute HIV-Infektion wird häufig übersehen. Dran denken, und bei Verdacht nicht mit dem H1V-test zögern!

Diagnostics of the HIV Infection The clinical picture of an acute HIV infection resembles that of mononucleosis with lymphadenopathy, fatigue and fever. In this phase, the infection can be diagnosed with certainty only through direct virus detection. During the subsequent latent phase, recurring or serious progressive skin manifestations from different illnesses, prominent candidiasis of the oral cavity and community acquired pneumonia frequently occur. Ulcerations in atypical locations of the gastrointestinal tract could also indicate an HIV infection. For cases of clear lymphopenia, an HIV infection should be definitely considered. Above all, the presence of non-Hodgkin's lymphoma is characteristic of the complete clinical picture of AIDS. An appropriate diagnostic test (antibody test or detection of HIV) is urgently indicated in situations that carry a high risk for HIV transmission. This applies, above all, to patients whose partner is HIV positive, to patients who frequently change sex partners, to prostitutes and to intravenous drug users.

[Pain therapy in cancer patients]. / Umfassende Palliativversorgung: Sieben Grundregeln für die Schmerztherapie.

Rigorous and appropriate pain therapy is a major element in palliative medicine, and affords the patient the possibility of being better able to organize the remaining time left to him. Every person has a legal right to, receive appropriate treatment for his/her pain, which in advanced disease states, is a multidimensional condition. This means that in addition to nursing staff and physicians, spiritual counselors, social workers, physiotherapists and volunteer helpers must be included in the pain-management team. Despite all our efforts, the ideal of complete freedom from pain is unrealistic. Nevertheless, the simple expression of solidarity with the terminally-ill patient, as is reflected by the provision of sympathetic attention, has in itself a positive impact on pain. By offering comprehensive and nationwide palliative care that is oriented to the needs of the terminal patient, society helps to provide a culture of the dying, and thus also of the living, that reflects humanistic principles.

A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. German ddI Trial Group.

OBJECTIVE: Zidovudine (ZDV) is the only antiretroviral drug which has been shown to reduce mortality in patients with symptomatic HIV disease, but its use is restricted by intolerance in a significant proportion of patients. Additionally, the efficacy of ZDV therapy appears to decrease after prolonged treatment particularly in the advanced stage of HIV disease. Therefore, alternative antiretroviral regimens for patients are needed. In this study, didanosine (ddI; 2',3'-dideoxyinosine), another HIV reverse transcriptase inhibitor, was evaluated. DESIGN: A total of 426 patients with AIDS or AIDS-related complex (ARC) who were intolerant to or clinically progressing on ZDV therapy and who had CD4+ cell counts < or = 150 x 10(6)/l were randomized to receive either a high (750 mg for bodyweight > or = 60 kg or 500 mg for bodyweight < 60 kg) or a low (200 mg and 134 mg, respectively) dose of ddI daily. SETTING: The patients were recruited from 31 German and Austrian AIDS clinical primary-care centres. RESULTS: The study was stopped after the second interim analysis due to a statistically significant difference in the incidence of pancreatitis (nine versus 26; relative risk, 2.92; P = 0.003) and neuropathy (28 versus 43; relative risk, 1.55; P = 0.05) in favour of the low dose. There was no difference between the low and high dosage groups in survival rate at 6 (80 versus 80%) and 12 months (61 versus 65%), number of deaths [82 (43.6 per 100 patient-years) versus 84 (44.4 per 100 patient-years)], progression from ARC to AIDS or to AIDS or death, or average number of new/recurrent opportunistic infections (2.8 versus 3.0 per patient). CONCLUSIONS: This study cannot conclude on ddI efficacy but it shows that in patients with advanced HIV disease for whom no alternative antiretroviral therapy is available and ddI therapy is considered, daily doses < 750 mg should be administered.

Sulfadiazine-associated nephrotoxicity in patients with the acquired immunodeficiency syndrome.

We performed a computerized search on sulfadiazine-associated nephrotoxicity reported in human immunodefiency virus (HIV)-infected patients in the international literature. Including an original case report, we summarized 35 acquired immunodefiency syndrome (AIDS) patients from 1987 to 1995 in an analysis comparing their features to historical HIV-negative controls from the 1940s and 1950s. Likely due to a high prevalence of potential risk factors, incidence of sulfadiazine-associated renal impairment was 1.9%-7.5% in AIDS patients and 1%-4% in HIV-negative controls. Its occurrence appeared to be delayed in HIV-infected patients with a median of about 3 weeks of medication compared with about 10 days in HIV-negative subjects. Correspondingly, the cumulative sulfadiazine dose at manifestation doubled in AIDS patients with a median of 84 g versus 40 g in controls. Patients usually presented with flank or lumbar pain, oliguria, and (macro) hematuria. Urinalysis showed typical "sheaves of wheat" crystalluria, erythrozyturia, and, less commonly, leukozyturia and proteinuria. Echogenic (mostly peripelvic) densities, renal stones, and hydronephrosis are frequent findings on ultrasound examination, whereas X-ray examination possesses a low diagnostic sensitivity. The principle aim of therapy in these patients is to (re)institute the physicochemical urinary solubility of sulfadiazine and its metabolites. For this purpose, forced rehydration and, most importantly, urine alkalinization proved to be effective measures without an absolute need to withhold the drug. Provided prophylactic and therapeutic recommendations are complied with, outcome of this drug-related side effect is usually excellent, and rare relapses will similarly respond well.

Amprenavir in combination with lamivudine and zidovudine versus lamivudine and zidovudine alone in HIV-1-infected antiretroviral-naive adults. Amprenavir PROAB3001 International Study Team.

OBJECTIVES: To compare the antiviral activity and safety of a new protease inhibitor, amprenavir (141W94) in combination with lamivudine and zidovudine, versus lamivudine and zidovudine alone in HIV-1 infected, antiretroviral-naive subjects. DESIGN: Subjects (n=232) with a CD4 T cell count of > or =200 cells/mm3, plasma HIV-1 RNA levels of > or =10000 copies/ml, and < or =4 weeks of prior nucleoside antiretroviral therapy, were stratified according to baseline plasma HIV-1 RNA level (10000-30000; 30000-100000; or >100000 copies/ml). Subjects received double-blind treatment with either 1200 mg amprenavir twice daily in combination with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily) (amprenavir/lamivudine/zidovudine) or matched placebo, lamivudine and zidovudine for 16 weeks. Thereafter, subjects with confirmed plasma HIV-1 RNA levels of > or =400 copies/ml could add open-label amprenavir or switch to other antiretrovirals and continue treatment for up to a minimum of 48 weeks. The primary endpoint of the study was defined as the proportion of subjects with plasma HIV-1 RNA of <400 copies/ml at 48 weeks. RESULTS: At 48 weeks, a significantly greater proportion of amprenavir/lamivudine/zidovudine subjects had plasma HIV-1 RNA levels <400 copies/ml than lamivudine/ zidovudine subjects in the overall population: 41 versus 3% (intent-to-treat missing equals failure analysis) (P<0.001); 93 versus 42% (as-treated analysis) (P<0.001); and within each of the three randomization strata (P<0.001). Subjects on amprenavir/lamivudine/zidovudine experienced longer time to event (permanent discontinuation of randomized therapy or viral rebound) than those on lamivudine/zidovudine (median of 33 versus 13 weeks; P<0.001). A significantly greater incidence of drug-related nausea, vomiting, rash and oral/perioral paresthesia was observed with amprenavir/lamivudine/zidovudine than with lamivudine/zidovudine. CONCLUSIONS: Amprenavir, in combination with lamivudine and zidovudine, has potent and durable antiviral activity in antiretroviral-naive subjects over 48 weeks. Amprenavir was safe and generally well tolerated.

Serum and cerebrospinal fluid levels of soluble intercellular adhesion molecule 1 (sICAM-1) in patients with HIV-1 associated neurological diseases.

We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1) in paired serum and CSF samples of 110 HIV-1-positive patients with and without neurological symptoms and 40 HIV-negative non-immune neurological controls, and in sera of 26 asymptomatic HIV-1-positive patients. Serum sICAM-1 levels in asymptomatic HIV-1-positive patients were significantly increased in comparison to HIV-negative controls. Moreover, they were significantly higher in HIV-1-positive patients with AIDS-defining diseases than in the asymptomatic HIV-1-positive group. In subgroups of patients with neurological disease, the highest serum values were found in HIV encephalopathy. CSF levels of sICAM-1 were elevated only in HIV-1-positive patients with neurological disease mainly due to passive diffusion through a defective blood-brain barrier. An sICAM-1 index was calculated as a measure for intrathecal production of sICAM-1 but showed no significant differences between patients with and without neurological involvement. However, increased levels of the sICAM-1 index were found in some patients with opportunistic CNS infection of bacterial or fungal origin. Serum and CSF levels of sICAM-1 correlated with neopterin levels, a marker of interferon-gamma-mediated macrophage activation and CSF sICAM-1 levels were inversely correlated to numbers of CD4+ T cells. Elevated serum sICAM-1 levels already in asymptomatic HIV-1-positive individuals add to the evidence for an early immune activation in HIV infection. With the further increase of serum and CSF s-ICAM-1 in patients with AIDS-defining diseases sICAM-1 could serve as a new surrogate marker similar to neopterin.

Ancillary benefits of Mycobacterium avium-intracellulare complex prophylaxis with clarithromycin in HIV-infected patients.

Because of the significant morbidity and mortality associated with opportunistic infections, prophylaxis has become routine practice in the management of immunocompromised patients such as those with AIDS. Clarithromycin, an antimicrobial agent with a broad spectrum of activity against most common respiratory pathogens as well as many protozoa, has proven to be effective for both treatment and prophylaxis of Mycobacterium avium-intracellulare complex (MAC) infection in AIDS patients. Results of a large multinational placebo-controlled study suggest that clarithromycin for MAC prophylaxis provides additional benefits. In this study, clarithromycin statistically significantly reduced the incidence of Pneumocystis carinii pneumonia (5.3% of clarithromycin recipients vs 10.0% of placebo recipients; p = 0.021), community-acquired pneumonia (7.1 vs 13.0%; p = 0.010), Giardia lamblia infection (0.9 vs 2.9%; p = 0.048), and neoplastic diseases (1.8 vs 4.1%; p = 0.010) in AIDS patients with CD4+ counts of < or = 100 cells/microliter.

Enhancing the response to interferon-alpha.

BACKGROUND: Though initially recognized as antiviral agents, it was soon demonstrated that certain neoplasms were particularly sensitive to interferon-alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treatment in AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identification of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. With a more comprehensive understanding how KS develops and which circumstances provide an increased virulence of this neoplasm in HIV-infected persons, a more subtle rationale for IFN-alpha treatment arose regarding the disorder of the endogenous IFN-system in HIV-positive individuals. Until recently IFN-alpha was the only therapy available for patients with chronic hepatitis C (CHC). However, no more than 30% of these patients show a sustained virological response. Initial therapy with a combination therapy of IFN-alpha and ribavirin turned out to be more effective than treatment with IFN-alpha alone. To ameliorate response rates in antiviral IFN-therapy a profound understanding of viral dynamics, as well as immunological conditions associated with viral persistence, seems to be essential. Within a conference of the European Society of Clinical Virology (ESCV), which took place in Hamburg from August 30 to September 2, 1998, and was entitled 'Progress in Clinical Virology IV', a satellite symposium was organized to evaluate the clinical results of special antiviral treatment options with IFN-alpha, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-alpha therapy. It focussed on HIV-related complications as coinfection with hepatitis C virus (HCV) and AIDS-KS, respectively. METHODS: A kinetic model of HCV infection based on principles established in studying HIV-1 infection was presented which is predictive for the outcome of IFN-alpha treatment. It involves different rates of velocity and compares the rates of acute clearance after different dosages of IFN-alpha application. Using the hypothesis to fit the changes in serum HCV RNA measured in a set of patients, it was found that 5 mIU daily dosing on average blocks 81% of HCV production/release, whereas 10 or 15 mIU blocks about 95% of HCV production/release. RESULTS: Only recently clinical data revealed a greater benefit of combination therapy with IFN-alpha and ribavirin compared to IFN-alpha alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after pretreatment with IFN-alpha monotherapy, sustained response was achieved in a 10-fold higher degree with a combination of IFN and ribavirin compared to patients retreated with IFN alone. In 1775 treatment-naive patients with CHC, response rates to the combination therapy was significantly higher in all patient groups with more than 60% of sustained virological response in patients with genotype 2 and 3, while patients with genotype 1 (poorer prognosis) benefit from extended combination treatment duration from 24 to 48 weeks (17 versus 29% of sustained virological response), respectively. CONCLUSIONS: As viral dynamics on one side and host immune response on the other feature as two landmarks on which the manifestation of viral persistence and chronic viral infections is established, some similarities of HCV and HIV disease are striking. An unusual endogenous IFN-alpha system is associated with both infections and is a negative prognostic factor to response to treatment with IFN-alpha in CHC as well as AIDS-KS. The consequences for treatment options with IFN are a combination with ribavirin in CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN-treatment in early disease followed by chemotherapy in advanced stages of KS.

Stavudine and the peripheral nerve in HIV-1 infected patients.

Stavudine (2',3'-didehydro-3'deoxythymidine) is a pyrimidine analogue that may be of great value in combination antiretroviral therapy (ART) for treating patients infected with human immunodeficiency virus type 1 (HIV-1). We assessed potential neurotoxic side effects by comparing peripheral nerve function in patients receiving ART including stavudine (n = 107) with that of patients receiving ART with zidovudine (n = 103). A cross-sectional analysis of electroneurographic data revealed no significant differences. In a follow-up examination of 31 patients newly started on ART with stavudine we observed no significant effects of the drug on electrophysiological measures. At a daily dose of 1.0 mg/kg the incidence of peripheral nervous system disease in our patients was about 10%. Repeated follow-up analysis of 13 patients on stavudine showed a significant reduction in sural nerve amplitude. Quantitative sensory testing in 13 patients revealed no systematic effect of stavudine on small nerve fibers. Peripheral nerve function in HIV-1 seropositive patients on ART with stavudine did not differ significantly from that in patients on ART with zidovudine. Therefore stavudine at a daily dose of 1.0 mg/kg is an alternative for patients who do not tolerate, or who have become resistant to zidovudine and can be recommended as a first-line drug in combination ART.

Magnetic stimulation of motor cortex in relation to fastest voluntary motor activity in neurologically asymptomatic HIV-positive patients.

Forty-two HIV-positive patients of various CDC stages without clinically evident neurological deficits were examined with transcranial magnetoelectrical stimulation (TMS). Cortical as well as cervical and lumbar root stimulation was performed after excluding peripheral neuropathies in comparison to an age- and sex-matched control group. Whereas central conduction times were normal, conduction between cervical or lumbar roots and muscle was prolonged. Results were correlated to those of a motor test battery, which revealed slowing of fast alternating movements similar to findings in extrapyramidal disorders. Data indicate that proximal parts of the peripheral nervous system and extrapyramidal structures are subclinically involved in early HIV infection whereas the fastest corticospinal projections remain intact.

Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy.

The diagnosis of definite progressive multifocal leukoencephalopathy (PML) has been a neuropathological domain. We reviewed all Human Immunodeficiency Virus Type 1 (HIV-1) seropositive patients in our institution between 01.01.1989 and 31.12.1994 and identified 20/823 cases with PML by clinical and imaging criteria. Diagnosis was neuropathologically confirmed in 5 cases. Diagnostic criteria included rapid onset (< 2 weeks) of multifocal neurological signs and symptoms, advanced immunosuppression and asymmetric uni- or multifocal white matter lesions without mass effect, contrast enhancement or cortical atrophy in magnetic resonance imaging (MRI). The overall incidence of PML was stable over the observation period (approximately equal to 2.5%). The mean age at onset (41.7 years) was significantly lower compared to HIV-1 seronegative PML patients (peak in the sixth decade of life), male patients prevailed (100%). Mean survival (3.9 months) was extremely short. Human polyoma virus JC (JCV) polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) demonstrated a considerable rate of possible cerebral co-infection with HIV-1 and JCV as well as subclinical infection with JCV. Therefore demonstration of JCV deoxyribonucleic acid by PCR in the CSF alone is not sufficient for clinical PML diagnosis. We present diagnostic criteria on the basis of epidemiological, neuroradiological and CSF parameters that allow us to make the clinical diagnosis of PML. Although quick and safe, routine stereotactic brain biopsy is not necessary to confirm the diagnosis.

A pathologically distinct new form of HIV associated encephalopathy.

We present the clinical, morphological and neuropathological findings in a 44-year-old male suffering from the acquired immunodeficiency syndrome (AIDS) (CDC stage IV C2) who presented with rapidly progressive right-side hemiparesis and developed hemianopia and aphasia. Scans showed multiple, not contrast-enhancing, not space-occupying echo-intensive lesions in T2-weighted MR-imaging. No hint for an opportunistic infection, necrotizing vasculitis or vascular disease was found. All therapeutic regimens failed and 8 weeks after onset of neurological symptoms the patient died because of cardiorespiratory arrest. Post-mortem examination excluded opportunistic infection, progressive multifocal leukoencephalopathy, lymphoma, vasculitis and ischemia of the brain. In the presence of an unusually high amount of HIV-infected macrophages at immunohistochemical examination, the overall pathological findings were atypical both for HIV encephalitis and HIV leukoencephalopathy. We describe a pathologically distinct new form of HIV associated encephalopathy.

Visceral leishmaniasis emerging as an important opportunistic infection in HIV-infected persons living in areas nonendemic for Leishmania donovani.

BACKGROUND: Visceral leishmaniasis is an important infection in patients infected with human immunodeficiency virus and living in areas endemic for Leishmania sp. Leishmaniasis, however, is rarely suspected in patients residing in nonendemic countries. METHODS: Retrospective case analysis of 15 patients with human immunodeficiency virus infection and leishmaniasis treated at seven German clinics. The clinicopathological features and the diagnostic role of biopsy and/or cytology as compared to serology were evaluated. RESULTS: All patients were severely immunocompromised. One patient was first diagnosed at autopsy. One patient with mucocutaneous disease was diagnosed by nasal biopsy. All others had amastigotes detected in bone marrow (13/13), liver (3/3), and gastrointestinal mucosa (4/4). Serology was positive in only 6 or 13. CONCLUSION: Visceral leishmaniasis is an important opportunistic infection in patients with acquired immunodeficiency syndrome and it must be ruled out in every patient with fever and/or pancytopenia and an appropriate travel history. Because serological diagnosis is often insufficient, pathologists must be aware of the association between human immunodeficiency virus infection and leishmaniasis. Diagnosis depends on detection of the parasite in submitted specimens.

Therapy of special HIV-associated diseases: HCV-HIV-co-infection and AIDS-related Kaposi's sarcoma - official satellite to the 7th European Conference on Clinical Aspects and Treatment of HIV-infection, October 23, 1999 in Lisbon, Portugal.

BACKGROUND: In the era of highly active antiretroviral therapy (HAART), certain complications of HIV-disease as e.g. opportunistic infections and Kaposi s sarcoma (KS) have significantly diminished. New insights in pathological pathways revealed the role of co-viruses as HHV-8 and HCV so that in our days AIDS-associated KS and chronical hepatitis C (CHC) in HIV-infected persons can be considered as the result of opportunistic infections with HHV-8 or HCV respectively. - Though the overall incidence of AIDS-KS is declining, it remains as a reason of severe disease complication and fatal outcome. Actual therapeutic strategies have to be evaluated regarding safety and efficacy as a major option, while cost-effectiveness of treatment and quality of life aspects for the patient must also be included to assess a successful disease management within the up to now merely palliative setting. HIV-infection evidently triggers the natural course of CHC in terms of more progressive liver disease. Otherwise there seems to be no clinical benefit of HAART on CHC. Until recently IFN-alfa treatment was the only therapy available for patients with CHC. As initial therapy with a combination of IFN-alfa and ribavirin turned out to be more effective than IFN-monotherapy in HCV-infected persons, it has now to be considered to include anti-HCV-combination treatment into the therapeutic program of HIV-HCV-coinfected patients under HAART. - Within the 7th European Conference on Clinical Aspects and Treatment of HIV-Infection, which took place in Lisbon from October 23 to 27 1999, a satellite symposium was organized to evaluate actual treatment options in the management of special HIV-associated complications focussing on AIDS-KS and HCV-HIV-coinfection. METHODS: To evaluate the safety and efficacy of IFN-alfa-2b and ribavirin combination therapy in patients with CHC, a total of 1773 treatment-naive patients was recruited in two phase III clinical trials. They were randomized in 4 treatment schedules to receive IFN-alfa-2b plus ribavirin or placebo for 24 weeks or 48 weeks respectively. Cost-effectiveness data compared treatment with liposomal daunorubicin and pegylated liposomal doxorubicin in AIDS-KS-patients within two phase III studies. The assumptions were a comparable efficacy, gastrointestinal toxicity, and frequency of opportunistic infections (OI). A quality-of-life-study on KS-treatment with pegylated liposomal doxorubicin (PLD, Caelyx(R)) was based on a phase III study with an overall median survival of 160 days for the patients, who completed questionnaires with 30 items specific for HIV-related diseases. The health-related quality-of life (HRQL) assessment and analysis includes 11 domains, in which improvements were calculated within a multiple analysis to be significant if they are higher than 10 (at a 0-100 scale). RESULTS: In 1775 treatment-naive patients with CHC, response rates to a combination therapy of IFN-alfa-2b with ribavirin was significantly higher in all patient groups with more than 60% of sustained virological response in patients with genotype 2 and 3, while patients with genotype 1 (poorer prognosis) benefit from extended duration from 24 to 48 weeks (17% versus 29% of sustained virological response). - Pegylated liposomal doxorubicin (PLD, Caelyx(R)) in the treatment of AIDS-related KS is more effective and less toxic than BV or ABV. Cost-effectiveness analysis suggests that PLD is preferable over liposomal daunorubicin, BV and ABV. Regarding the HRQL-assessment, PLD came out to be superior in 9 of 11 domains tested, with the greatest improvement in general health and pain relief. CONCLUSIONS: As the combination therapy of IFN-alfa-2b with ribavirin is the first treatment in CHC, there is an urgent need to consider the therapeutical strategies in this field in HCH-HIV coinfected patients. (ABSTRACT TRUNCATED)

Glycyl-glutamine improves in vitro lymphocyte proliferation in AIDS patients.

BACKGROUND: Glutamine (Gln) is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for Gln is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glycyl-glutamine on lymphocyte proliferation we investigated its influence on lymphocytes of AIDS patients and healthy controls under stimulation with different mitogens. MATERIAL AND METHODS: Lymphocytes were collected from 11 adult patients suffering from AIDS according to the CDC definition and from 7 adult healthy donors. Glutamine (Gln) and glycyl-glutamine (GlyGln), respectively, were added to cell cultures at concentrations between 0 and 1.0 mmol/l. ConA or SAC served as T or B cell mitogens, respectively. Plasma amino acid levels were determined. RESULTS: Proliferation upon ConA-stimulation with GlyGln-supplementation was similar to Gln-supplementation and peaked dose dependently at 1.0 mmol/l. When SAC was used Gln seemed slightly superior to GlyGln with a peak at 0. 4 mmol/l but the results did not reach the level of statistical significance. An identical response pattern was demonstrated in HIV-patients, however at lower absolute proliferation rates. Normal values could not be restored. Overall, the use of either source of glutamine in equimolar concentrations did not result in major differences of proliferation. Glutamine and glycin plasma levels did not differ between HIV patients and controls. CONCLUSION: GlyGln can be used as a substitute for Gln with regard to lymphocyte proliferation. Lymphocytes from AIDS patients show, as controls do, an enhanced proliferation under supplementation either glutamine source. Supplementation of GlyGln might enhance lymphocyte proliferation and thus improve immunity.

Pneumocystis carinii pneumonia in the Federal Republic of Germany in the era of changing antiretroviral therapy - IDKF 13 -. German AIDS Study Group (GASG/IdKF).

BACKGROUND: Pneumocystis carinii pneumonia (PCP) is one of the most common AIDS defining diagnoses. METHODS: In a prospective observational trial all cases of Pneumocystis carinii pneumonia (PCP) were evaluated. Patients with and without PCP-prophylaxis were compared for symptoms, efficacy, side effects and mortality at week 4 and 26. RESULTS: 293 patients developed a PCP episode. Patients with no prophylaxis had a significant lower CD4 cell count and a more severe clinical status at time of diagnosis. This was pronounced in the group with first positive HIV test at time of diagnosis. There was no difference in the rate of successful treatment between both groups. At week four a tendency to a better survival in the group with prophylaxis was observed, however this changed to a trend to a better survival at week 26 for the group without prophylaxis. CONCLUSION: Even in the era of highly active antiretroviral treatment many patients present with PCP. Nearly 60% of patients presented without antiretroviral treatment or PCP-prophylaxis. Nearly 25% of all patients had their first HIV-test at time of PCP diagnosis.