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.

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.

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.

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.

[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.

HIV-related non-Hodgkin's lymphoma: CHOP induction therapy and interferon-alpha-2b/zidovudine maintenance therapy.

In a prospective multicenter study 68 out of 158 patients with HIV infection and malignant lymphoma were assigned to a risk-adapted induction therapy using the following algorithm: High-risk patients fulfilled 2 of 3 criteria: T4 lymphocytes <50/microL; WHO activity index 3 or 4; pre-existing AIDS-defining opportunistic infection. Normal-risk patients received 4 to 6 cycles of CHOP chemotherapy; those that achieved complete remission (CR) received zidovudine (500 mg/d) and interferon-alpha maintenance therapy (5 million units three times a week) for one year. High-risk patients received low-dose CHOP or vincristine/prednisone chemotherapy. Supportive care was performed with pentamidine inhalation and G-CSF. Intrathecal (it) methotrexate was given for CNS prophylaxis. The median survival was 634 days for 38 patients of the normal-risk group and 129 days for 30 patients of the high-risk group. 18 high-risk patients treated with low-dose CHOP had better survival (156 days) than 12 patients treated with vincristine/prednisone (72 days p=0.044). 68% of the patients in the normal-risk group achieved complete remission. 5 out of 18 high-risk patients treated with low-dose CHOP achieved complete remission. Three normal-risk patients developed fatal opportunistic infections during chemotherapy. Immune parameters deteriorated after CHOP induction and partially recovered with maintenance treatment. We conclude that the normal-risk patients survived longer than reported in most published studies. Toxicity was low. Low-dose CHOP seems to be superior to vincristine/prednisone therapy in high-risk patients.

Acute and long-term efficacy of antituberculous treatment in HIV-seropositive patients with tuberculosis: a study of 36 cases.

Thirty-six consecutively observed HIV-seropositive patients with tuberculosis, including 31 patients with AIDS, who received antituberculous treatment, were followed up to evaluate its efficacy. Treatment with standard antituberculous regimens was intended except when an individual's condition required a modified therapeutic approach. Therapeutic failure occurred in five patients (14%) while on treatment, one also had a post-treatment relapse. Treatment failure was associated with drug resistance and non-compliance in three patients and in another two, both of whom died early in the course of their disease, with HIV-related conditions other than tuberculosis. The median relapse-free post-treatment follow-up time in 24 patients in whom treatment did not fail was 13 months (range 4-67). Standard antituberculous treatment is highly effective in the immediate and long-term treatment of HIV-related tuberculosis provided that drug susceptibility and treatment compliance are confirmed.

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.

Extracerebral toxoplasmosis in AIDS. Histological and immunohistological findings based on 80 autopsy cases.

Despite the great amount of literature concerning toxoplasmic encephalitis in AIDS patients, little is known about extracerebral toxoplasmosis. Therefore we conducted a study of 80 autopsy cases to estimate the frequency of extracerebral toxoplasmosis. A control group of 50 cases was completely negative for all markers applied. In 35 of the 80 AIDS-cases (43.7%), organisms could be detected. In 13 cases (16.2%) there was an extracerebral toxoplasmosis; 4 cases (5%) showed only extracerebral involvement and in 9 cases (11.2%), extracerebral toxoplasmosis occurred in combination with cerebral manifestations. In 22 cases (27.5%), only cerebral toxoplasmosis was found. The following organs were involved: cardiac muscle (15%), lungs (6.2%), liver (5%), pancreas (5%), gastrointestinal tract (6.2%), adrenal glands (5%), lymph nodes (5%) and testis (3.7%). In individual cases further organs, not mentioned above, were involved. Pseudocysts could be demonstrated within necroses and inflammatory foci by conventional staining, whereas trophozoites became apparent only immunohistologically.

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.