PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis.

OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.

The effect of timing of antiretroviral therapy on CD4+ T-cell reconstitution in the intestine of HIV-infected patients.

Whether and to what extent gut mucosal CD4(+) T cells of HIV-infected patients can be restored by combination antiretroviral therapy (cART) is not yet fully resolved. We studied absolute numbers, differentiation, and activation of mucosal CD4(+) T cells at different stages of HIV infection and assessed the effect of timing of cART initiation on this cell population. Mucosal CD4(+) T-cell numbers were severely reduced at all stages of chronic infection, but normal in patients with acute infection. In patients with initiation of cART during chronic HIV infection, mucosal CD4(+) T cells restored to less than half of the numbers in controls. However, in patients who initiated cART during acute HIV infection, mucosal CD4(+) T-cell numbers were fully preserved and markers of microbial translocation and inflammation reversed to normal. The proportion of mucosal effector memory CD4(+) T cells normalized only if cART was initiated at >350 CD4(+) T cells per µl blood but not with delayed treatment. In conclusion, mucosal CD4(+) T-cell numbers can be preserved if cART is initiated in acute HIV infection. In chronically HIV-infected patients, early cART improves mucosal CD4(+) T-cell differentiation but cannot prevent the persistent lack of total CD4(+) T cells.

Clindamycin-primaquine for pneumocystis jiroveci pneumonia in renal transplant patients.

BACKGROUND: Trimethoprim/sulfamethoxazole (TMP/SMX) is considered first-line therapy for pneumocystis jiroveci pneumonia (PCP) in renal transplant patients. Alternatives have not been formally studied. Clindamycin-primaquine (C-P) is effective in HIV-associated PCP, but data in renal transplant patients are lacking. PATIENTS AND METHODS: Retrospective cohort study of 57 consecutive renal transplant patients who developed PCP and were treated with C-P (n = 23) or TMP/SMX (n = 34). RESULTS: A non-significantly higher failure rate was observed in patients on C-P due to lack of efficacy (30.4 versus 20.6%, p = 0.545). The difference was more pronounced in severe PCP (60 versus 37.5%, p = 0.611) and a significantly lower efficacy of C-P was seen when used as salvage therapy. The two patients who had received C-P after not responding to TMP/SMX failed this regimen, but all seven patients who had failed initial treatment with C-P and had been switched to TMP/SMX were cured (p = 0.028). No treatment-limiting adverse reactions were reported for patients on C-P while six patients (17.6%) on TMP/SMX developed possibly related treatment-limiting toxicity (p = 0.071). However, in only two patients adverse events were definitely related to TMP/SMX (5.9%). CONCLUSIONS: Clindamycin-primaquine appears to be safe and well tolerated for treating PCP in renal transplant patients but is probably less effective than TMP/SMX, the standard regimen. However, our data indicates that C-P represents an acceptable alternative for patients with contraindications or treatment emergent toxicities during TMP/SMX use. Notably, TMP/SMX was also acceptably tolerated in most patients. TMP/SMX remains an effective salvage regimen in case of C-P failure.

Pharmacokinetic profile in late pregnancy and cord blood concentration of tipranavir and enfuvirtide.

The data on the use of tipranavir and enfuvirtide in pregnancy are very limited. We performed a pharmacokinetic profile in a pregnant woman with multidrug-resistant HIV-1 infection at 37 weeks gestation. Tipranavir levels were in the therapeutic range and the cord blood concentration at delivery was relatively high when compared with other protease inhibitors. No enfuvirtide was detected in the fetal compartment. Tipranavir and enfuvirtide were successfully used in pregnancy, but possible toxicities must be kept in mind.

Toxoplasmic encephalitis in AIDS-patients before and after the introduction of highly active antiretroviral therapy (HAART).

Toxoplasmic encephalitis (TE) continues to be a severe health problem despite the introduction of highly active antiretroviral therapy (HAART). To identify predictors for development of TE we compared demographic, clinical and diagnostic variables in AIDS patients with TE before (n = 102) or after the introduction (n = 70) of HAART at the Charité University Medicine in Berlin, Germany. Interestingly, patient characteristics did not differ significantly in the pre- and post-HAART groups. Sixty-eight percent of patients had CD4-cell counts of <50/µl. Outcome after treatment with pyrimethamin plus sulfonamides or clindamycin (47% each) did not differ; adverse reactions were more frequent in patients receiving sulfonamides than in those receiving clindamycin (25% vs. 10.5%; p = 0.02). Interestingly, patients in the post HAART group had not received (82.9%) or had not taken HAART adequately (17.1%). Concurrent diagnosis of TE and HIV was significantly more often in the post- compared to the pre-HAART group (49 vs. 26%, respectively; p > 0.001). Thus, despite the introduction of HAART, awareness of opportunistic infections in HIV patients is warranted. High rates of unawareness of HIV infection should make public health efforts focus on early identification of HIV infection and initiation of and compliance with HAART.

The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive Individuals.

OBJECTIVE: This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated. METHODS: Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2). RESULTS: 168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209). CONCLUSIONS: Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.

Stellar and primordial nucleosynthesis of 7Be: measurement of 3He(alpha,gamma)7Be.

The 3He(alpha,gamma)7Be reaction presently represents the largest nuclear uncertainty in the predicted solar neutrino flux and has important implications on the big bang nucleosynthesis, i.e., the production of primordial 7Li. We present here the results of an experiment using the recoil separator ERNA (European Recoil separator for Nuclear Astrophysics) to detect directly the 7Be ejectiles. In addition, off-beam activation and coincidence gamma-ray measurements were performed at selected energies. At energies above 1 MeV a large discrepancy compared to previous results is observed both in the absolute value and in the energy dependence of the cross section. Based on the available data and models, a robust estimate of the cross section at the astrophysical relevant energies is proposed.

Kaletra single agent HAART after intolerance of NRTI- and NNRTI-containing regimens following kidney transplantation.

We report on a patient who received a diagnosis of HIV infection following kidney transplantation some years earlier. As a result of intolerance and failure of nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI)-containing regimens, he was started on Kaletra single agent HAART. Kaletra was well tolerated and resulted in sustained viral load suppression below the limit of detection for at least 36 months.

12C+12C fusion reactions near the Gamow energy.

The fusion reactions 12C(12C,alpha)20Ne and 12C(12C,p)23Na have been studied from E=2.10 to 4.75 MeV by gamma-ray spectroscopy using a C target with ultralow hydrogen contamination. The deduced astrophysical S(E)* factor exhibits new resonances at E< or =3.0 MeV, in particular, a strong resonance at E=2.14 MeV, which lies at the high-energy tail of the Gamow peak. The resonance increases the present nonresonant reaction rate of the alpha channel by a factor of 5 near T=8x10(8) K. Because of the resonance structure, extrapolation to the Gamow energy EG=1.5 MeV is quite uncertain. An experimental approach based on an underground accelerator placed in a salt mine in combination with a high efficiency detection setup could provide data over the full EG energy range.

Concomitant use of gastric acid-reducing agents is frequent among HIV-1-infected patients receiving protease inhibitor-based highly active antiretroviral therapy.

OBJECTIVE: The aim of the study was to assess the frequency of the concurrent use of gastric acid-reducing agents among HIV-1-infected patients treated with highly active antiretroviral therapy (HAART) combinations. METHODS: An anonymous, semistructured, self-administered questionnaire was consecutively distributed among HIV-1-infected patients at routine visits to specialized HIV clinics. The questionnaire contained 17 items asking specifically for information on current antiretroviral treatments and the use of gastric acid-reducing agents as well as demographic data. RESULTS: A total of 424 patients in 12 centres participated in the study: 85% were male, 88% were of German nationality, 82% were >35 years of age and 201 (47.4%) were receiving a protease inhibitor (PI)-containing HAART regimen. Of these, 74 (37%) had received an acid-reducing drug within the previous 6 months and 43 (58%) were currently still on it. Two-thirds of patients (64.9%) were treated with proton-pump inhibitors (pantoprazole, omeprazole or esomeprazole) and 56% of patients on PI-containing regimens had been taking these drugs for longer than 2 months and up to a maximum of 3 years. The majority of patients (77%) had received the prescription for the acid-reducing drugs from their HIV specialist and the remaining patients had received over the counter (OTC) medication or prescriptions from other medical personnel. CONCLUSIONS: A substantial subset of patients treated with HAART combinations, including those on PI-containing regimens, were using concomitant acid-reducing drugs, most often proton-pump inhibitors. As negative drug-drug interactions between some of the (boosted) PIs and gastric acid-reducing agents have recently been reported, HIV physicians should take this into account when prescribing PI-containing HAART combinations in order to avoid an additional risk of treatment failure.

Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin's disease: results of a multicenter study.

BACKGROUND: The purpose of the study was to evaluate the outcome of Hodgkin's disease (HD) in patients infected with the human immunodeficiency virus (HIV) with respect to the use of highly active antiretroviral therapy (HAART). MATERIALS AND METHODS: This cohort study included patients with HIV-HD diagnosed from June 1984 to February 2004. Patients treated in the pre-HAART era (1984-1996) were compared with those belonging to the HAART era (1997-2004). RESULTS: Of 66 patients with HIV-HD, 47 (71%) presented with stage III/IV disease and 38 patients (58%) with an AIDS-defining illness. Fifty-nine of 66 patients (89.4%) underwent curative intended chemotherapy. Patients receiving HAART (n = 34) had a significantly better 2-year overall survival (OS) than those not receiving HAART (74% versus 30%, P <0.001). The 2-year OS of HAART-responders was 88% compared with 19% in patients without HAART-response (P = 0.0002). By multivariate analysis patients without HAART had a 5.6-fold higher risk for 3-year mortality [HR 5.6, 95% confidence interval (CI) 2.20-14.26]. Three-year mortality was significantly higher in patients without complete remission (HR 4.40, CI 1.77-10.99), with stage III/IV HD (HR 4.64, CI 1.31-16.49) and with CD4 cells <200/microl (HR 2.69, CI 0.99-7.33). CONCLUSIONS: Use of HAART significantly improved the overall survival in patients with HIV-HD.

[Brain metastases of lung cancer]. / Hirnmetastasen beim Lungenkarzinom.

Cerebral metastases are a frequent complication of lung cancer. They often determine patients' prognosis and need urgent therapeutic intervention. Based on histologic type, former therapies, age and performance of the patient, the number of cerebral lesions and the extracerebral tumour activity, individualized treatments are applied. For patients who suffer from non-small cell lung cancer and a single CNS lesion the best results can be achieved if they are surgically resected or receive radiosurgery. Their survival time can be markedly increased in comparison to patients who undergo whole brain irradiation. If multiple metastases are seen in CT or MRI, whole brain irradiation is the therapy to choose. Furthermore it should be initiated if small cell lung cancer metastasizes to the brain. More aggressive local treatment options appear promising, but a clear role for them has not yet been defined. Systemic chemotherapy gains more attention in the treatment of small and non-small cell lung cancer with brain metastases. How to increase the efficacy through simultaneous application of chemo- and radiotherapy is tested in current trials. This article gives an overview on clinical presentation and diagnosis of cerebral metastases in lung cancer and reviews current treatment options.

[Detection of airways stenoses: comparison of virtual and flexible bronchoscopy]. / Detektion von Atemwegsstenosen: Vergleich der virtuellen mit der flexiblen Bronchoskopie.

PURPOSE: To compare virtual with flexible bronchoscopy for the detection of bronchial stenoses. MATERIALS AND METHODS: In a retrospective study, we compared the results of 26 patients, who had clinical suspected pathologies of the tracheobronchial airways and underwent both flexible bronchoscopy and multislice CT with 3D surface rendering of the airways. Flexible bronchoscopy and virtual bronchoscopy were compared as to the rate of detecting bronchial stenoses. For statistical analysis, we divided the tracheobronchial tree in the following sections: trachea, 2 main bronchi, 6 lobar bronchi, 18 segmental bronchi and 36 subsegmental bronchi, corresponding to 63 bronchial sections for each patient (on average) and a total of 1638 bronchial sections for all 26 patients. We graded the bronchial stenosis as less than 50 %, as 50 to 95 % and as complete obstruction. RESULTS: Virtual bronchoscopy detected 25 bronchial stenoses, while flexible bronchoscopy only revealed 17 stenoses. Stenoses with a diameter less than 50 % were found with virtual bronchoscopy 14 times and with flexible bronchoscopy 10 times. Stenoses with a diameter between 50 and 95 % were detected 7 and 4 times, respectively, and complete obstructions 4 and 3 times, respectively. Tracheobronchial stenoses were well recognized with virtual bronchoscopy. Moreover, the virtual method enabled the visualization of high-grade stenoses and post-stenotic areas that could not be passed by the fiberoptic bronchoscope. Virtual bronchoscopy detected stenoses at a higher rate but the difference was not statistically significant (stenoses < 50 %: p = 0.352, 50 - 95 %: p = 0.339, complete obstruction: p = 0.696). CONCLUSION: Virtual bronchoscopy is a useful non-invasive method for the diagnostic evaluation of the tracheobronchial tree. In comparison with flexible bronchoscopy, virtual bronchoscopy is superior in revealing high-grade stenoses and visualizing post-stenotic areas.

Comparison of metabolic abnormalities 48 weeks after switching from highly active antiretroviral therapy containing a non-nucleoside reverse transcriptase inhibitor to Trizivir versus continued highly active antiretroviral therapy.

Forty patients participating in the TRIZAL study were treated with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen before being randomly assigned either to continue their baseline therapy or to switch to a triple nucleoside regimen. No difference was observed in treatment efficacy between the two groups, and total cholesterol was observed to improve significantly in the switch group. Switch maintenance may be an appropriate strategy in patients treated with an NNRTI.

Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection.

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment.

The objective of the present trial was to compare the efficacy, safety, and tolerability of moxifloxacin (400 mg) given intravenously (i.v.) once daily followed by oral moxifloxacin (400 mg) for 7 to 14 days with the efficacy, safety, and tolerability of co-amoxiclav (1.2 g) administered by i.v. infusion three times a day followed by oral co-amoxiclav (625 mg) three times a day, with or without clarithromycin (500 mg) twice daily (i.v. or orally), for 7 to 14 days in adult patients with community-acquired pneumonia requiring initial parenteral therapy. A total of 628 patients were enrolled and assessed by evaluation of their clinical and bacteriological responses 5 to 7 days and 21 to 28 days after administration of the last dose of study medication. Although the trial was designed, on the basis of predefined outcomes, to demonstrate the equivalence of the two regimens, the results showed statistically significant higher clinical success rates (for moxifloxacin, 93.4%, and for comparator regimen, 85.4%; difference [Delta], 8.05%; 95% confidence interval [CI], 2.91 to 13.19%; P = 0.004) and bacteriological success rates (for moxifloxacin, 93.7%, and for comparator regimen, 81.7%; Delta, 12.06%; 95% CI, 1.21 to 22.91%) for patients treated with moxifloxacin. This superiority was seen irrespective of the severity of the pneumonia and whether or not the combination therapy included a macrolide. The time to resolution of fever was also statistically significantly faster for patients who received moxifloxacin (median time, 2 versus 3 days), and the duration of hospital admission was approximately 1 day less for patients who received moxifloxacin. The treatment was converted to oral therapy immediately after the initial mandatory 3-day period of i.v. administration for a larger proportion of patients in the moxifloxacin group than patients in the comparator group (151 [50.2%] versus 57 [17.8%] patients). There were fewer deaths (9 [3.0%] versus 17 [5.3%]) and fewer serious adverse events (38 [12.6%] versus 53 [16.5%]) in the moxifloxacin group than in the comparator group. The rates of drug-related adverse events were comparable in both groups (38.9% in each treatment group). The overall incidence of laboratory abnormalities was similar in both groups. Thus, it is concluded that monotherapy with moxifloxacin is superior to that with a standard combination regimen of a beta-lactam and a beta-lactamase inhibitor, co-amoxiclav, with or without a macrolide, clarithromycin, in the treatment of patients with community-acquired pneumonia admitted to a hospital.

A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients.

The efficacy, safety, and tolerability of voriconazole and fluconazole were compared in 391 immunocompromised patients with mycology- and biopsy-proven esophageal candidiasis. Primary efficacy analysis (256 patients) of esophageal treatment as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole. The 95% confidence interval for the difference in success rates ranged from -1.0% to 7.5%. The overall safety and tolerability of both antifungals were acceptable. Fewer patients discontinued voriconazole treatment because of insufficient clinical response (4 patients [2.0%] vs. 5 patients [2.6%]). More patients discontinued voriconazole than fluconazole treatment because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). The most frequent adverse events (23%) with voriconazole were mild, transient visual disturbances. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as fluconazole in the treatment of biopsy-proven esophageal candidiasis in immunocompromised patients.

Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS.

OBJECTIVE: To evaluate the safety and efficacy of a fixed 25mg pyrimethamine--500mg sulfadoxine combination plus 15mg folinic acid given twice weekly for the prevention of relapses of Pneumocystis carinii pneumonia (PCP) and primary episodes of toxoplasmic encephalitis. METHODS: Ninety-five HIV-infected patients with successfully treated PCP and without history of toxoplasmic encephalitis were enrolled between January 1990 and October 1995 in a single-arm open-label prospective study. No patient was receiving highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. Efficacy was analysed on an "as-treated" basis. RESULTS: Five patients (5.3%) suffered a PCP relapse while on study medication, three of whom had been non-compliant. No relapse occurred in the first year. Probabilities of freedom from relapse were 0.96 after 24 months and 0.90 after 36 months. Of 69 patients positive for anti-toxoplasma IgG antibodies, one (1.5%) developed cerebral lesions compatible with toxoplasmic encephalitis after 50 months. Cutaneous allergic reactions were observed in 16 patients (16.8%) resulting in permanent discontinuation in six patients (6.3%). Two patients (2.1%) developed serious adverse reactions (Stevens-Johnson syndrome), both of whom had continued prophylaxis despite progressive hypersensitivity reactions. CONCLUSIONS: The prophylactic regimen used is effective in preventing PCP relapses and toxoplasmic encephalitis. The regimen appears to be safe. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance of the regimen. Efficacy and safety compare favourably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients unable to tolerate approved regimens.