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Objectives - We compared clinical long-term course and outcome in all AIDS patients admitted to our outpatient department from January, 1989 to June, 1998 with toxoplasma encephalitis (TE) as first AIDS-defining infection (n=106) and in 106 patients with Pneumocystis carinii pneumonia (PCP) as first AIDS-defining disease. Material and methods -The 2 groups were matched with respect to age, sex, risk group, degree of immunodeficiency as measured by CD4 cell counts and duration of HIV-1-positivity. TE was diagnosed radiologically and by response to treatment. Results - Forty-three TE patients surviving the first TE symptoms >14 months developed dementive symptoms, leucoencephalopathy in imaging procedures and died from dementia. In contrast only 5 patients surviving PCP for an equally long period showed dementive symptoms. Conclusion - Cerebral infections like toxoplasma encephalitis (TE) may negatively influence HIV-1-activity so far latent in the brain.

167 HIV-positive patients (155 men, 12 women; mean age 31 [18-61] years) with CD4 lymphocyte counts below 250/microliter every 4 weeks received 300 mg pentamidine per aerosol inhalation during out-patient visits, as prophylaxis against Pneumocystis carinii. 89 patients were clinically in the AIDS stage and 33 in the AIDS-related complex (ARC) stage. 29 patients had a lymphadenopathy syndrome, while 16 were asymptomatic. 130 patients received primary prophylaxis, while 37 who had previously had an attack of Pneumocystis carinii pneumonia were given pentamidine as secondary prophylaxis. During a mean observation period of 8 months three patients developed Pneumocystis carinii pneumonia (1.7%): their CD4 lymphocyte count was under 20/microliters. Pentamidine inhalation reduced the incidence of a first attack of pneumonia to 0.18% per month and recurrence to 0.32% per month. These figures confirm the great effectiveness of primary and secondary prophylaxis with pentamidine inhalation.

Objectives Predictors of the efficacy of highly active antiretroviral therapy (HAART) have been investigated in several studies. To increase current knowledge, the study aimed to acquire comprehensive data over an extended observation time, to obtain information on possible performance differences among individual drugs, and to identify factors with influence on the initial response to a HAART regimen and the sustainability of the response. Methods The data were obtained from a prospective, single University Medical School HIV cohort. Clinical, laboratory, and treatment parameters for 475 patients were collected over 4.5 years. HAART efficacy was determined by analysis of variance and multivariate survival analysis. Results The overall initial complete response (CR) (

Unbehandelt entwickeln die meisten Patienten mit einer chronischen Hepatitis B oder C schwere, zum Teil lebensbedrohliche Komplikationen. Doch die Diagnose dieser Lebererkrankungen ist eine Herausforderung, weil viele HBV-und HCV-Infektionen symptomlos verlaufen. Lesen Sie, wer besonders gefahrdet ist und bei wem Sie die entsprechende Diagnostik vornehmen sollten.

We have comparatively evaluated Quantiplex version 3.0 and version 2.0 on 133 plasma samples and a repetitive dilution series. Version 3.0 yielded higher human immunodeficiency virus RNA values, and the ratio of version 3.0 results to version 2.0 results decreased from 3.47 below 1,000 copies/ml to 1.97 above 50,000 copies/ml [linear regression, log (version 3.0) = 0.915 + 0.871 × log (version 2.0); r 2 = 0.952].

Background: Though initially recognized as antiviral agents, it was soon demonstrated that certain neoplasms were particularly sensitive to interferon-α (IFN-α). Indeed, the initial success of systemic IFN-α 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-α treatment arose regarding the disorder of the endogenous IFN-system in HIV-positive individuals. Until recently IFN-α 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-α and ribavirin turned out to be more effective than treatment with IFN-α 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-α, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-α 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-α treatment. It involves different rates of velocity and compares the rates of acute clearance after different dosages of IFN-α 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-α and ribavirin compared to IFN-α alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after pretreatment with IFN-α 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-α system is associated with both infections and is a negative prognostic factor to response to treatment with IFN-α 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.

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 ≥200 cells/mm3, plasma HIV-1 RNA levels of ≥10000 copies/ml, and ≤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 ≥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 Results At 48 weeks, a significantly greater proportion of amprenavir/lamivudine/zidovudine subjects had plasma HIV-1 RNA levels 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.

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.

The objective of this study was to assess endogenous granulocyte colony-stimulating factor (G-CSF) serum levels in HIV-seropositive individuals with persistent neutropenia or acute febrile infection. Serum levels of G-CSF were measured by enzyme-linked immunoabsorbent assay. HIV-seropositive subjects (n = 28) with afebrile neutropenia (< 1000 neutrophils/microliter) showed low G-CSF serum levels (i.e., median was below the detection limit) not different from those of healthy volunteers (n = 66) or nonneutropenic HIV-seropositive controls (n = 75). In contrast, patients with acute myeloid leukemia and afebrile neutropenia from chemotherapy (n = 17) demonstrated markedly elevated G-CSF levels (median, 264 pg/ml; p < 0.0001). However, HIV-seropositive patients with pneumonia (n = 17) showed increases of G-CSF serum levels (median, 152 pg/ml; p < 0.0001) similar to HIV-seronegative patients (n = 17) with pneumonia (median, 123 pg/ml; p = 0.97). The results suggest that there may be a contribution of low G-CSF serum levels to persistent neutropenia in HIV-seropositive individuals. Moreover, the different G-CSF serum levels in HIV-seropositive individuals in response to neutropenia or acute febrile inflammation suggest different mechanisms for the regulation of G-CSF.

Our aim was to establish the frequency and the longitudinal pattern of MAC culture positivity in late stage HIV-infected patients. Two other aims were to analyse risk factors for progression from localized to systemic disease and the value of PCR diagnosis using blood specimens. A total of 107 patients were recruited to be followed for 32 weeks. Prior MAC treatment and CD4 > 100/microliters were exclusion criteria. A total of 56 patients showed M. avium in at least 1 culture. 10/37 patients with MAC detected by culture first in 'non-sterile' specimens (stool, sputum) and urine progressed to systemic disease as determined by positive blood culture. Risk factors associated with this progression were a high symptom score at baseline, lymphadenopathy, anaemia, and low platelets. PCR was less sensitive than culture in detection of M. avium in blood specimens: Only 7/29 patients with positive blood cultures had a positive PCR at the same time. We conclude that symptomatic patients with advanced HIV-infection have a high frequency of MAC detection. Progression from localized to systemic culture positivity is associated with risk factors. Early 'pre-emptive' therapy is discussed.

Background Disseminated infection with Mycobacterium avium complex is the most common opportunistic infection in patients with advanced stages of the acquired immunodeficiency syndrome (AIDS). We studied the efficacy and safety of prophylactic treatment with clarithromycin, a macrolide antibiotic. Methods We conducted a randomized, placebo-controlled, double-blind study of clarithromycin in patients with AIDS in the United States and Europe. Entry criteria included blood cultures that were negative for M. avium complex, a Karnofsky performance score of 50 or higher, a CD4 cell count of 100 or less per cubic millimeter, and a life expectancy of at least six months. Results After the first interim analysis, the study was stopped. M. avium complex infection developed in 19 of the 333 patients (6 percent) assigned to clarithromycin and in 53 of the 334 (16 percent) assigned to placebo (adjusted hazard ratio, 0.31; 95 percent confidence interval, 0.18 to 0.53; P

The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients.

Differential and sometimes contradictory effects have been described for tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) on replication of human immunodeficiency virus type 1 (HIV-1). The authors examined individual and coordinate action of these cytokines on HIV-1 expression, and on apoptosis of HIV-1-infected host cells by determination of reverse transcriptase activity in cell culture supernatant, expression of HIV-1-RNA and production of p24 antigen in the promonocytic cell line U937 and its persistently HIV-1-infected clone U1. Apoptosis was demonstrated by typical cleavage of cellular DNA at internucleosomal regions in promonocytic and T-lymphocytic cell lines. TNF-alpha alone markedly stimulated HIV-1 replication in U1 cells at the transcriptional and on the translational level. Exclusive application of IFN-gamma only slightly enhanced HIV-1 expression, whereas it synergistically potentiated stimulatory effects of TNF-alpha. Both cytokines also synergistically induced apoptosis in HIV-1-infected host cells. Co-ordinate action of TNF-alpha and IFN-gamma is suggested to represent an important mechanism for disease progression in HIV infection. These findings demonstrate that cytokine effects on viral expression may vary depending on their single or combined application.

Background Treatment of ocular toxoplasmosis in HIV-infected patients with standard drug regimes (Pyrimethamine, Clindamycine, Sulfonamides) is very often complicated by sideeffects and adverse reactions. On the other hand, maintenance therapy must be continued life long, because of the high recurrence rates. Atovaquone (Hydroxynaphthoquinon) is tolerated excellently and is very effective against tachyzoits of toxoplasma gondii and its cysts. Patient History and clinical findings A 49-year-old homosexual man with AIDS developed an allergic rash after beeing treated with a course of Pyrimethamine and Clindamycine for unilateral, bifocal ocular toxoplasmosis for 13 days. Therapy with Atovaquone 3×750 mg/d was instituted and within 8 days the infiltrates healed leaving retinochorioidal scars. Therapy and clinical course During maintenance therapy with Atovaquone (3×750 mg/d) two relapses occurred, the first after 2 months and the second after 8 months. The recurrences were successfully treated by increasing the dosage of Atovaquone to 4×750 mg/d and the addition of Trimethoprime/Sulfamethoxazol and Clindamycine/Pyrimethamine respectively. Reexposition was tolerated without an allergic reaction. Unter maintenance therapy with Pyrimethamine the patient was free of recurrences for another 4 months until he died. Conclusions Atovaquone is an effective and well tolerated substance for the treatment of ocular toxoplasmosis. In contrast to earlier reports, two recurrences occured under maintenance therapy. It cannot be excluded that the patient was incomplient and did not take the tablets according to our presription. Future clinical investigations have to control the efficacy of Atovaquone in the therapy of ocular toxoplasmosis

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-γ-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.

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.

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.

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.

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.

Eight episodes of rifabutin-associated anterior uveitis in AIDS patients are reported. Uveitis developed after two weeks to nine months of medication, commonly when rifabutin was administered along with clarithromycin and/or fluconazole. Recovery was closely correlated to suspending rifabutin early, while less dependent on total rifabutin dose or epidemiological patient characteristics. In two cases, discontinuation of rifabutin alone relieved ocular inflammation. Repeated exposure to rifabutin was successful with a reduced dosage in three patients.

Opportunistic diseases (OD) are still the most common cause of death in patients with HIV infection. The occurrence of OD is the most important single prognostic factor for survival. While in the pre-HAART era, many patients died of the wasting syndrome, today, ever more patients suffer from obesity and its consequences. Tuberculosis is widespread among those affected with HICV, and when treating it must be remembered that tuberculostatic agents and antiretroviral drugs interact with cytochrome P450. Until recently, the combination of rifampicin with protease inhibitors and non-nucleoside reverse-transcriptase inhibitors was contraindicated. Now, however, the Centers for Disease Control (CDC) has updated its recommendations for treatment.

HIV-associated cardiopathies have a poor prognosis, in particular in patients with low CD4 counts or accompanying encephalopathy. The pathogenesis is multifactorial and the therapeutic options are limited. Pericardiac effusions are also associated with a poor prognosis. Other cardiac manifestations of HIV infection are opportunistic infections, infectious endocarditis (in particular i.v. drug use), neoplasia, and pulmonary hypertension. Premature development of vascular diseases is often observed in patients receiving combination antiretroviral treatment. A number of antiretroviral agents, but also antibiotics and chemotherapeutic agents have cardiotoxic side effects. Echocardiography is a good, noninvasive and inexpensive screening method that should be performed at least once a year in all asymptomatic HIV patients.

Since its inception, highly active antiretroviral therapy (HAART) has undergone constant further development. The German Aids Society (DIG), but also the British HIV Association (BHIVA) and the North American Department of Health and Human Services (DHHS) have all issued recommendations on HAART. A comparison of these recommendations reveals that despite the many points they have in common, gaps in our knowledge, and shortcomings in both the diagnosis and treatment of HIV infections still persist.

In the year 2003, the basis of antiretroviral treatment comprising nucleoside and nucleotide reverse transcriptase inhibitors (NRTI, NNRTI, NtRTI) and protease inhibitors (PI) will be extended to include entry inhibitors (EI). A representative of this class of drugs, enfurvitide (T20), is about to receive official approval. In the meantime, initial data on long-term treatment with tenofovir, which has been available in Germany since February 2002, have become available. Further medications are in the pipe-line of clinical development, for example, the NRTI emtricitabine (FTC) and the Pis amdoxovir and Atazanavir. Results from studies employing immunomodulatory approaches have so far proved disappointing. In contrast, a number of smaller studies on vaccination have provided promising data. Recommendations for antiretroviral treatment of HIV infection were updated in the summer of 2002.

The role of opportunistic diseases in daily clinical routine is once again expanding. The signs of a change in the trend towards increasing incidence observed in the year 2000 have unfortunately been confirmed. The risk of contracting an opportunistic infection can be estimated with the aid of the CD4 cell count and the viral burden. CM viremia can also be employed as a predictor if highly active antiretroviral therapy (HAART) fails to cure cytomegaly. In the age of HAART, the spectrum of diseases resulting in hospitalization of HIV patients has undergone a change. A notable increase has been observed in hospitalizations for toxic side effects of medication, respiratory infections and liver diseases, in particular hepatitis. Following the introduction of HAART, the mortality rate of HIV-infected patients dramatically decreased, but the results of an American study show that, since 1999. It is on the increase again.

Since the HAART, primary and secondary prophylaxis, a better understanding of HIV infection and, last, but not least, improved patient compliance with treatment due to a facilitated treatment regimen, have all contributed to achieving a reduction in the number of opportunistic diseases. However, they are no longer decreasing as rapidly as before, but appear to have leveled off. In the first months of HAART a so-called immune reconstitution syndrome, an acute variegated clinical picture may appear, which must be differentiated diagnostically from intolerance of HAART.

The nucleosidal reverse transcriptase inhibitors (NRTI), the protease inhibitors (PI) and the non-nucleosidal reverse transcriptase inhibitors remain the pillars of antiretroviral therapy (ART). In the spring of 2002, they were joined by a representative of a further class of substances, the nucleotidal reverse transcriptase inhibitors (NTRTI). The use of PI, but also of other substances, is associated with undesired effects, in particular on lipid and glucose metabolism. The aim of treatment is to achieve maximum reduction in the amount of virus in the blood. The question as to the timing of treatment--early or late--continues to arouse controversial discussion.

Ten years ago, the first clinical trial on the tolerability and efficacy of didanosine (ddl) was initiated in German therapeutic centers. At that time, AIDS patients in an advanced stage of the disease who failed to respond to monotherapy with AZT, were treated with ddl. However, the form of presentation of ddl, namely buffered powder, was poorly tolerated. In the meantime, galenical improvements have been made. Today, treatment with ddl is possible at a daily dose of one EC (enteric-coated) capsule. Given this in this form, the substance is highly effective, and the absorption of indinavir, ciprofloxacin, and ketoconazole is in no way impaired.

Since the middle of the nineteen-nineties, the number of opportunistic infections has been on the decrease. For the most part, this is due to HAART and optimized primary and secondary prophylactic measures. Nevertheless, these infections have not lost any of their clinical relevance, for example, in patients in whom they are index conditions for the HIV diagnosis, or in whom immune reconstitution under HAART fails. New therapeutic concepts that improve the patients chances of surviving have been developed. On the basis of current results it is now recommended that secondary prophylaxis be forgone when under HAART the CD4 cell count increases to above 200/microL.

For antiretroviral therapy (ART) nucleosidereverse transcriptase inhibitors (NRTI), protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are available, and are used in combination treatments. The use of PI is associated with new side effects, in particular affecting lipid metabolism. The objective of treatment continues to be a maximum reduction of the viral load. The question whether to treat the HIV early on or later is under controversial discussion. Simplified therapeutic regimens making possible single or twice-daily doses and the use of small numbers of tablets represent a major advance in ART.

Seit 1996 sind Dreifachtherapien im Einsatz, die HI-Viren zwar nicht eradizieren, aber dennoch gut bekampfen. Mit der zunehmenden Vertraglichkeit der antiretroviralen Substanzen ruckte ein fruher Therapiestart wieder in den Vordergrund. Eine aktuelle Studie zeigt, dass damit die Mortalitat von HIV-Patienten erheblich sinkt. Diese Ergebnisse haben die Empfehlungen der Fachgesellschaften beeinflusst. Lesen Sie, wann und wie die HAART erfolgen sollte.

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.Subjects (n=232) with a CD4 T cell count ofor =200 cells/mm3, plasma HIV-1 RNA levels ofor =10000 copies/ml, andor =4 weeks of prior nucleoside antiretroviral therapy, were stratified according to baseline plasma HIV-1 RNA level (10000-30000; 30000-100000; or100000 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 ofor =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 of400 copies/ml at 48 weeks.At 48 weeks, a significantly greater proportion of amprenavir/lamivudine/zidovudine subjects had plasma HIV-1 RNA levels400 copies/ml than lamivudine/ zidovudine subjects in the overall population: 41 versus 3% (intent-to-treat missing equals failure analysis) (P0.001); 93 versus 42% (as-treated analysis) (P0.001); and within each of the three randomization strata (P0.001). 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; P0.001). A significantly greater incidence of drug-related nausea, vomiting, rash and oral/perioral paresthesia was observed with amprenavir/lamivudine/zidovudine than with lamivudine/zidovudine.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.

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.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.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.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.

Following the first international conference in 1999, twice as many new antiretroviral substances are in the early clinical or preclinical phase of investigation as are currently approved for ART in Germany. These data are almost certainly not complete, and the number of "candidates" will be larger rather than smaller. Nevertheless they send a clear message. Antiretroviral treatments guided by therapeutic pessimism are anything but up to date. This applies to inadequate dual treatments or the delayed use of ART. The plethora of new medications with no, or virtually no, cross-resistance vis-a-vis previously approved substances renders in admissible any reasons advanced for delayed or reserved treatment. The present article has been written also for those therapists who, for the reasons set out above, have so far greatly delayed, or have provided only "half-hearted", treatment. In the near future, ART will comprise not only the inhibition of HIV replication, but will also deal with immune reconstruction. As in the last 15 years, antiretroviral therapeutic strategies will be the signposts and pacemakers for the treatment of other infectious diseases, too. Not least of the conditions included are such important chronic viral ailments as hepatitis B or C, which have just successfully crossed the combination therapy threshold. It is to be hoped that a maximum number of the substances presented here will pass the proving period leading a full-blown antiretroviral medication.

For antiretroviral therapy (ART) nucleoside reverse transcriptase inhibitors (NRTI), protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) are available, and are used in combination treatments. The use of PI is associated with new side effects, in particular affecting lipid metabolism. The objective of treatment continues to be a maximum reduction of the viral load. The question whether to treat the HIV early on or later is under controversial discussion. Simplified therapeutic regimens making possible single or twice-daily doses and the use of small numbers of tablets represent a major advance in ART.

Hepatitis C is one of the world's leading infectious diseases. The interferon-ribavirin combination therapy is the new standard for the treatment of hepatitis C in naive and relapse patients. Virological sustained response rates can be more than doubled by the IFN-ribavirin combination therapy compared to IFN-monotherapy and treatment duration can be reduced to six months in many cases. The IFN-ribavirin combination therapy has a high relative benefit in patients with unfavorable predictive parameters like high viral load, HCV genotype-1 infection and compensated liver cirrhosis. Anemia is the most important side effect of the guanosin analogue ribavirin. There are no official therapeutic recommendations for non-responder patients at present. These patients should be treated within controlled clinical trials. Monotherapy with PEG(pegylated)-interferons and combination therapies with PEG-interferons and ribavirin are the most promising future therapeutic options.

Kryptokokkosen werden durch Cryptococcus neoformans, der einzigen humanpathogenen Spezies der Gattung Cryptococcus (C.) hervorgerufen. Dieser kapselbildende Sprospilz last sich anhand biochemischer und genetischer Kriterien in zwei Varietaten C. neoformans var.neoformans und var.gattii unterteilen. Auch klinisch ist diese Unterteilung sinnvoll, da deutliche Unterschiede bezuglich der Epidemiologie und Pathogenitat bestehen [14, 20]. C.neoformans var. neoformans ist die fur HlV-infizierte Patienten relevante Spezifitat, da dieser Keim vorwiegend Erkrankungen bei Individuen mit verminderter T-Zell-Funktion hervorruft. So werden weltweit etwa 80–90% der klinisch manifesten Infektionen mit diesem Erreger bei HIV-positiven Patienten beobachtet [5]. Als typische opportunistische Infektionen gehoren extrapulmonale Kryptokokkosen zu den AIDS-definierenden Erkrankungen [3]. C. neoformans var. neoformans kommt ubiquitar in der Umwelt vor und last sich in hohen Keimzahlen aus den Ausscheidungen von Vogeln isolieren. Die Infektion wird vorwiegend durch Inhalation erregerhaltigen Aerosols akquiriert, nachfolgend kann es zu einer hamatogenen Streuung mit Absiedlung in verschiedenen Organsystemen kommen [11]. Die Inzidenz von Kryptokokkosen bei HIV-Patienten zeigt erhebliche geographische Unterschiede. So sind in manchen Landern Afrikas mehr als 15% [4], in den USA etwa 10% der HIV-Patienten betroffen [13]. Die bisher vorliegenden Angaben aus Europa weisen betrachtliche Unterschiede auf, so wird aus Frankreich [6] eine Inzidenz von 4,8–7,8% berichtet, wahrend Schatzungen aus England [9] und Danemark [10] von einer Inzidenz von 4% bzw. 1,7% ausgehen. Insgesamt scheinen Kryptokokkosen in Europa seltener aufzutreten als beispielsweise in den USA. Umfassende Daten zur Haufigkeit von Kryptokokkosen bei HIV-positiven Patienten in Deutschland liegen bislang nicht vor.

Moderne antiretrovirale Behandlungsstrategien ermoglichen nicht nur eine gute Wirksamkeit sondern auch deutlich vereinfachte Einnahmeintervalle. Was vor wenigen Jahren noch eine Wunschvorstellung war, namlich die einmal tagliche Dosierung ist moglich geworden. Schrittmacher fur diese patientenfreundliche und compliancesteigernde Vereinfachung ist ein neuer nicht nukleosidaler reverse Transkriptase Inhibitor (NNRTI), das Efavirenz.