Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066).

INTRODUCTION: There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions. MATERIALS AND METHODS: The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies). CONCLUSION: The review presented here is a translation of a short version of the German-Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.

Excellent long-term survival of 170 patients with Waldenström's macroglobulinemia treated in private oncology practices and a university hospital.

The purpose of this study was to compare treatment and outcome of patients with Waldenström's macroglobulinemia (WM) in four private oncology practices (PP) and a university hospital (UH) in southwest Germany. We retrospectively reviewed the charts of all patients with WM of the last two decades of four PP in Mannheim, Heidelberg, Karlsruhe, and Speyer and the Department of Hematology of the University of Heidelberg. One hundred seventy patients could be identified, 74 from PP, 96 from the UH. Median age was 63.3 years. Patients from PP were older (median 65.3 vs. 62.5 years, p = 0.01). Only 54 % of patients from PP have received treatment during the observation time, as compared to 78.1 % of the UH (p < 0.001). In PP, 35 % of treated patients have received rituximab, as compared to 62.6 % of the patients of the UH (p < 0.001). Sixty percent of treated patients of PP have received bendamustine, as compared to only 8 % of the patients of the UH (p < 0.001). Time to first treatment was significantly shorter in patients from the UH compared to PP (median 13.7 vs. 52.9 months, p = 0.05). A trend towards a better overall survival was observed for patients treated with a rituximab-containing first-line regimen. The International Prognostic Scoring System for WM had significant prognostic value. Median overall survival was 25.0 years and did not differ between PP and UH. Despite different treatment strategies between PP and UH today overall survival of patients with WM is excellent, and better than previously reported.

The rainbow cohort: 96 week follow-up of saquinavir-containing regimens in previously antiretroviral therapy (ART)-naive and pre-treated but protease inhibitor (PI)-naive HIV-infected patients.

OBJECTIVE: We have previously reported data from the German cohort of the multinational observational prospective RAINBOW survey which assessed the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r)-containing regimens over 48 weeks in routine clinical practice. This analysis presents data from antiretroviral (ART)-naive and pretreated but protease inhibitor (PI)-naive patients treated in a long-term one line (96 weeks) follow-up of the initial study. METHODS: All ART- and PI-naive patients from the initial RAINBOW cohort who had recorded data to one line 96 weeks of treatment were eligible for inclusion in the current analysis. Efficacy assessments included the proportion of patients with HIV-1 RNA <50 and <400 copies/mL and changes in CD4 cell count from baseline to week 96. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 96. For evaluation of efficacy, intent-to-treat analysis, in which missing values were recorded as failure (ITT), and last-observation-carried-forward (LOCF) analysis were used. Metabolic parameters were assessed using LOCF analysis. RESULTS: The analysis included 175 ART-naive and 109 pretreated but PI-naive patients. After 96 weeks, a similar proportion of patients in the ART-naive and in the pretreated but PI-naive group had HIV-1 RNA levels <400 copies/mL (68.0% and 70.6% [ITT], respectively; 96.6% and 90.8% [LOCF], respectively). The proportion of patients with HIV RNA <50 copies/mL was higher in the ART-naive group compared with the pretreated but PI-naive group (61.1% and 56.9% [ITT], respectively; 84.0% and 75.2% [LOCF], respectively). Median change in CD4 cell count from baseline to week 96 was +263 cells/mm3 (IQR 170; 384. LOCF; p<0.0001) in the ART-naive group, and one line +181 cells/mm3 (IQR 60; 309. LOCF; p<0.0001) in the pretreated but PI-naive group. Treatment was well tolerated, with only 2.5% of patients withdrawing from treatment due to side effects. There were no clinically relevant changes in liver enzyme levels. Overall total cholesterol, triglyceride, and low- and high-density lipoprotein levels increased to week 96, although levels remained within normal ranges in the majority of ART-naive and pretreated patients. CONCLUSIONS: This follow-up analysis confirms the long term efficacy and tolerability of SQV/r in ART-naive and pretreated but PI- naive patients in the real-life clinical setting.

Safety and efficacy after switch to a saquinavir-containing antiretroviral regimen in protease inhibitor pretreated HIV-positive patients.

OBJECTIVE: the RAINBOW survey is a multinational observational study assessing the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r), using the 500 mg film-coated SQV formulation, in routine clinical practice. This analysis presents data from the German subgroup of protease inhibitor (PI)-pretreated, but SQV-naive patients. METHODS: multicenter, prospective, open-label, 48 week cohort study. Efficacy assessments included the proportion of patients with HIV-1 RNA <50 and <400 copies/mL and changes in CD4 cell count from baseline to week 48. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 48. RESULTS: a total of 426 patients were included in the analysis. The proportion of patients with HIV RNA levels <50 copies/mL at week 48 was 60.3 % (compared with 31.7% at switch to SQV/r) (intent-to-treat, last observation carried forward analysis). After 48 weeks, median CD4 count increased by +61 cells/mm3 from baseline (p<0.01) and 60.3% of patients achieved HIV-1 RNA <50 copies/mL. Median changes in fasting triglyceride levels (stratified according to baseline level) at week 48 were: +14 mg/dL (IQR -8; 57) for patients with baseline triglyceride <200 mg/dL; -50 mg/dL (IQR -139; 0) for baseline triglyceride 200-750 mg/dL, and -656 mg/dL (IQR -1024; 0) for baseline triglyceride >750 mg/dL (p<0.01 for all). Median changes in fasting total cholesterol (TC) levels (stratified according to baseline) were +16 mg/dL (IQR -3; 43) for patients with baseline TC <200 mg/dL (p<0.01), -3 mg/dL (IQR -25; 25) for baseline TC 200-300 mg/dL (p = 0.4), and -47 mg/dL (IQR -87; -4) for baseline TC >300 mg/dL (p<0.01). No significant changes in liver enzymes or bilirubin were observed. SQV treatment was discontinued in 22% of patients, 6% due to side effects. CONCLUSIONS: these data confirm the efficacy and tolerability of SQV/r in PI-experienced, SQV-naive patients treated in a real-life clinical setting. Of particular relevance are the improvements in triglycerides and TC levels observed in patients with baseline grade III-IV elevations.

Safety and efficacy of a saquinavir-containing antiretroviral regimen in previously ART-naïve or pretreated but protease inhibitor-naïve HIV-positive patients.

BACKGROUND: The RAINBOW survey is a multinational observational study assessing the tolerability and efficacy of ritonavir-boosted saquinavir (SQV/r), using the 500-mg film-coated SQV formulation, in routine clinical practice. This analysis presents data from the German subgroup of antiretroviral therapy (ART)-naïve and pretreated but protease inhibitor (PI)-naïve patients. METHODS: This was a multicenter, prospective, open-label, 48-week observational cohort study. Tolerability assessments included changes in liver enzymes and lipid levels from baseline to week 48. Efficacy assessments included changes in the proportion of patients with HIV-1 RNA <50 and <400 copies/ml, and changes in CD4 cell count from baseline to week 48. RESULTS: The analysis included 275 ART-naïve and 179 pretreated but PI-naïve patients. The proportion of ART-naïve patients achieving <50 copies/ml by 48 weeks was 53.1% by intent-to-treat (ITT) analysis and 67.3% using last observation carried forward (LOCF) analysis. In pretreated but PI-naïve patients, the proportions achieving <50 copies/ml by 48 weeks were 53.1% (ITT) and 70.4% (LOCF). The median increase in CD4 count at week 48 was +174 cells/mm3 (interquartile range [IQR] 86, 265) in the ART-naïve group and +100 cells/mm3 (IQR 0, 209) in the pretreated but PI-naïve group (p < 0.01 for both; LOCF). Drug-related adverse events were reported in 7.6% of ART-naïve and 2.8% of pretreated but PI-naïve patients. Treatment with SQV/r was stopped in 21.5% of ART-naïve and 17.9% of pretreated but PI-naïve patients (due to side effects in 3.3% and 2.8%, respectively). There were no clinically relevant changes in liver enzyme levels. Overall, the total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein levels increased to week 48, although the levels remained within normal ranges in the majority of patients. CONCLUSIONS: The results of this observational cohort study of treatment with the 500-mg tablet formulation of SQV are consistent with high efficacy and tolerability results seen in controlled studies of SQV/r. This analysis confirms that SQV/r is effective and well tolerated in ART-naïve and pretreated but PI-naïve patients in 'real-world' clinical settings.

Treatment during primary HIV infection does not lower viral set point but improves CD4 lymphocytes in an observational cohort.

OBJECTIVE: To investigate if early treatment of primary HIV-1 infection (PHI) reduces viral set point and/or increases CD4 lymphocytes. METHODS: Analysis of two prospective multi-centre PHI cohorts. HIV-1 RNA and CD4 lymphocytes in patients with transient treatment were compared to those in untreated patients. Time to CD4 lymphocyte decrease below 350/ microl after treatment stop or seroconversion was calculated using Kaplan-Meier and Cox-PH-regression analyses. RESULTS: 156 cases of PHI were included, of which 100 had received transient HAART (median treatment time 9.5 months) and 56 remained untreated. Median viral load (563000 cop/ml vs 240000 cop/ml; p<0.001) and median CD4 lymphocyte (449/ microl vs. 613/ microl; p<0.01) differed significantly between treated and untreated patients. Median viral load was 38056 copies/ml in treated patients (12 months after treatment stop) and 52880 copies/ml in untreated patients (12 months after seroconversion; ns). Median CD4 lymphocyte change was +60/ microl vs. -86/ microl (p = 0.01). Median time until CD4 lymphocytes decreased to <350/ microl (including all patients with CD4 lymphocytes <500/ microl during seroconversion) was 20.7 months in treated patients after treatment stop and 8.3 months in untreated patents after seroconversion (p<0.01). Cox-PH analyses adjusting for baseline VL, CD4 lymphocytes, stage of early infection and symptoms confirmed these differences. CONCLUSIONS: Treatment during PHI did not lower viral set point. However, patients treated during seroconversion had an increase in CD4 lymphocytes, whereas untreated patients experienced a decrease in CD4 lymphocytes. Time until reaching CD4 lymphocytes <350/ microl was significantly shorter in untreated than in treated patients including patients with CD4 lymphocytes <500/ microl during seroconversion.

Hepatotoxicity in patients prescribed efavirenz or nevirapine.

AIM: For several years Nonnucleoside reverse transciptase inhibitors (NNRTIs) in antiretroviral therapy have been associated with hepatic side effects. Particularly the hepatotoxic potential of Nevirapine is well analysed today. We performed a prospective, multicenter study to compare the hepatotoxicity of Efavirenz (EFV) with that of Nevirapine (NVP) and to investigate further risk factors. MATERIAL AND METHODS: The study included HIV-1-infected patients from five clinics and private medical practices in southwestern Germany who initiated an antiretroviral therapy with NVP or EFV between July 1998 and December 2001. Among 296 patients in total, 151 received EFV and 145 received NVP. Laboratory tests during the course of treatment included liver enzymes, HIV-RNA and CD4 cell-count. Additionally, signs of clinical hepatitis were recorded. Hepatotoxicity was graded in the manner of Sulkowsky et al. (2000), who used a scale modified from that of the AIDS Clinical Trials Group. RESULTS: Hepatitis C virus and hepatitis B virus were detected in 10.1% and 4.1% of patients, respectively. The overall rate of severe hepatotoxicity (grade 3 to 4 elevations in aspartate aminotransferase and/or alanine aminotransferase) was 2 of 151 (1.3%) in patients prescribed EFV and 3 of 145 (2.1%) in patients prescribed NVP. Mild-to-moderate hepatotoxicity (grade 2 elevation) was observed in 6.0% (EFV) and 3.4% (NVP) of patients. Incidence of mild-to-moderate and severe hepatotoxicity did not differ significantly between the study groups. 3 of 14 patients (2.1%) with grade 2 elevation of liver enzymes (LEE) and 4 of 5 patients (80%) with grade 3 to 4 LEE were symptomatic. Only risk factor for the development of mild-to-moderate hepatotoxicity was hepatitis C coinfection. CONCLUSION: Increases of liver enzymes during therapy with NVP or EFV are not unusual, but are mostly mild-to-moderate and asymptomatic. LEE occurs just as frequent in patients prescribed EFV as in patients prescribed NVP.

[High incidence of non-AIDS-defined cancers among HIV-infected patients in Germany. A 3-year nationwide review]. / Hohe Inzidenz nicht AIDS-definierender Neoplasien bei HIV-infizierten Patienten in Deutschland. Ein 3-jähriger bundesweiter Uberblick.

OBJECTIVE: It was the main aim of this study to obtain data on the epidemiology of AIDS- and not AIDS-defined malignancies in HIV-positive persons, the results to provide an epidemiological overview and to be the basis for further research initiatives. Additionally it sought to gain an impression of the realities of treatment of patients with HIV-associated malignant tumors in Germany. PATIENTS AND METHODS: Over a period of 3 years (from the beginning of 2000 to the end of 2002) data were retrospectively collected on the incidence of malignant tumors in HIV-positive patients. A questionnaire was sent to all members of the German Working Party of Physicians in Private Practice Treating HIV-Infected Patients, all members of the Association of Haematologists and Oncologists in Private Practice, and all out-patient HIV clinics in Germany. The questionnaires were sent to a total of 949 practices/clinics. The data were collected on all AIDS- and not-AIDS-defined haematological malignancies and all AIDS- and not-AIDS-defined solid malignant tumors in HIV-positive patients, as well as on time of diagnosis of the malignancy, tumor stage, tumor treatment and response to treatment. RESULTS: 380 data sets on 376 patients of 50 practices/clinics were included in the analysis (four patients had two malignant tumors). 180 malignant neoplasms (47%) were AIDS-defined: 89 Kaposi's sarcomas, 82 aggressive B-cell lymphomas and 9 invasive cervical carcinomas. The aggressive B-cell lymphomas consisted of 19 cases of Burkitt's lymphoma, 8 of Castleman's disease and 12 of primary cerebral malignant lymphoma. Of the 200 (52.6%) not-AIDS-defined malignant tumors 133 were 133 solid tumors, 40 of them anal carcinoma (20% of all not-AIDS-defined malignancies) and 67 haematological malignancies, 22 of these Hodgkin's lymphoma (11.0% of all not-AIDS-defined malignancies). The incidence of anal carcinoma is estimated to be 34 (95% CI 24-470) per 100 000 patient-years, that of Hodgkin's lymphoma 19 (95% CI 12-28) per 100 000 patient-years. CONCLUSIONS: This study indicates that over a period of 3 years there was a very high incidence of not-AIDS-defined malignancies. Of special note is the high incidence of anal carcinoma and Hodgkin's lymphoma, compared with their incidence among the entire German population.

Long-term consequences of treatment interruptions in chronically HIV-1-infected patients.

OBJECTIVE: To evaluate the long-term effects of antiretroviral treatment (ART) interruptions on metabolic, immunological, virological and clinical outcomes in chronically HIV-1 infected patients. METHODS: Multi-centric, prospective, controlled 24-month cohort study in HIV-1 infected patients interrupting ART once or several times and for at least two weeks. Patients were compared to a frequency-matched control group continuing on ART. RESULTS: A total of 399 HIV-1 infected patients were included, among them 133 patients with treatment interruption (TI) and 266 control patients. Baseline characteristics were well matched. Median baseline CD4 cell count was 379/microl in TI-patients and 410/microl in control patients (p = ns). Median duration of the first TI was 1.1 months, and 37 % of patients had two or further TI's. Whereas CD4 cell count in control patients had increased significantly by a median of 67/microl at month 24 (p<0.0001), median CD4 cell count at month 24 in the TI-patients did not differ significantly from baseline. However, two-year AIDS-free survival was not significantly different between TI- and control patients. Liver enzymes and blood lipids improved significantly during TI. CONCLUSION: TI was associated with a significant immunological disadvantage at 24-month follow-up compared to continued ART. In this relatively immunocompetent cohort, however, TI's did not lead to an increased risk of disease progression within two years of follow-up.

[Rashes in HIV-infected patients undergoing therapy with nevirapine or efavirenz]. / Arzneimittelexantheme bei Therapie der HIV-Infektion mit Efavirenz und Nevirapin.

Efavirenz and nevirapine are frequently used drugs in antiretroviral therapy. Rashes are common side effects of these drugs. In this study, we examined the characteristics of efavirenz- and nevirapine-associated rashes. This prospective nonrandomized multicenter study included 662 HIV-infected patients (efavirenz: 325, nevirapine: 337) to determine incidence, duration, cross-reactivity, and outcome upon reexposure. Of the treated patients, 4.5% (n=30) developed rashes (nevirapine: 2.4% and efavirenz: 6.4%). In four patients treatment was not interrupted. Three patients were re-exposed to the initial drug without any side effects. Therapy with nevirapine or efavirenz does not have to be interrupted if rashes exhibit no blistering, mucosal manifestations, or systemic signs.

Evaluation of a didanosin-containing regimen including genotypic resistance testing: an open-label, multicenter study.

PURPOSE: To show Didanosin in a new formulation as a once-a-day capsula as a well-tolerated and effective HIV-therapy when used in a protease sparing regimen including genotypic resistance pattern in blood, semen and cerebrospinal fluid before and during treatment. METHOD: Two groups of 58 patients, each containing 9 patients who had not been previously treated with any antiretroviral medication, and 49 patients heavily pretreated for 3,7 (DDI group) and 2,8 (non-DDI group) years, have been followed up for at least half a year. A group of 24 patients taking a special combination of Didanosin plus Efavirenz and Stavudine have been analysed with genotypic resistance testing concerning viral load response and resistance pattern under therapy. RESULTS: Suppression of plasma HIV-1 RNA to <50 copies/mL and <500 copies/mL in the DDI group was achieved in 74% and 84% of the pretreated patients, respectively, and in 100% of the naive patients after 24 weeks. In the non-DDI group suppression was achieved in 59% and 69% of the pretreated patients, respectively, and in also 100% of the naive patients. The viral load reduction in the DDI containing regimen at week 24 was 1.7 log subset 10 for the pretreated and 3,4 log subset 10 for the naive patients. In the non-DDI group, the reduction was 1.5 for the pretreated and 4,0 for the naive patients. CD4 cell counts increased from 440 to 517 cells/microL at week 24 for the pretreated, and from 171 to 289 for the naive patients in the DDI containing regimen. In the other group, cells increased from 396 to 406 for the pretreated and from 155 to 321 for the naive patients. In each group, 12 patients discontinued treatment; 4 patients in the DDI group and 7 patients in the non-DDI group because of adverse events. There were no AIDS-defining events in the antiretroviral-treated patients in both groups. 16 patients of the special combination group (DDI, D4T and EFV) were evaluated for more than 24 weeks. Suppression of HIV-1 RNA to <50 copies /mL were found in 75% of the naive and 43% of the pretreated patients. No relevant mutations were found during treatment. CONCLUSION: The new formulation of Didanosin as a once-a-day capsula in a protease sparing regimen was well-tolerated, effective in reducing viral load and in preventing AIDS-defining events. The combination of DDI, D4T and EFV proved to be a potent therapy without developing relevant mutations.

Evaluation of an efavirenz-containing regimen: an open-label, multicenter study.

PURPOSE: Efavirenz (EFV) has been shown to be a highly effective HIV therapy in antiretroviral-naïve patients when used with nucleoside reverse transcriptase inhibitors. METHOD: The study participants were 314 patients, 45 of whom had not been previously treated with any antiretroviral medication. The other patients were heavily pretreated for about 3 years (1,047 days); 34 with two nucleoside reverse transcriptase inhibitors, 147 with triple therapy, and 88 with a quadruple regimen. RESULTS: Suppression of plasma HIV-1 RNA to <50 copies/mL and <500 copies/mL was achieved in 56% and 72% of the pretreated patients and in 82% and 91% of the naïve patients, respectively, at week 80 (intention-to-treat analysis: noncompleters = failure: 10% and 15% and 20% and 22%, respectively). The viral load reduction at week 80 was 0.7 log(10) for the pretreated patients and 2.6 log(10) for the naïve patients. CD4 cell counts increased from 386 to 474 cells/microL at week 80 in the pretreated group and from 264 to 431 in the naïve patients. 118 patients discontinued the treatment due to adverse events (37 patients due to nervous system symptoms and 15 patients because of exanthema). There were no AIDS-defining events in the group of antiretroviral-treated patients. CONCLUSION: EFV in combination with nucleoside reverse transcriptase inhibitors as antiretroviral therapy was potent and effective in reducing viral load, mainly in treating therapy-naïve patients and in preventing AIDS-defining events.

[Left bundle-branch block and primary benign heart tumor]. / Linksschenkelblock und primärer benigner Herztumor.

The electrocardiogram (ECG) of a 56-year-old woman suffering from insomnia and nervousness revealed left bundle branch block, an ECG two years previously having been normal. Echocardiography showed a perimyocardial space-occupying lesion in the area of the left ventricle. Magnetic resonance imaging demonstrated a 6 x 6 x 7 cm solid tumour, which could not be separated from the myocardium of the dorsal portion of the ventricle and the left atrial wall. Coronary angiography demonstrated a few small atypical vessels originating from the right coronary artery. An endomyocardial biopsy was equivocal. An exploratory thoracotomy revealed a large, livid tumour which could not be resected because it involved a large area of the left ventricle and left atrium. Surgical biopsy showed a cavernous haemangioma. The subsequent course (ten months' follow-up) has so far been unremarkable.