The Intelence aNd pRezista Once A Day Study (INROADS): a multicentre, single-arm, open-label study of etravirine and darunavir/ritonavir as dual therapy in HIV-1-infected early treatment-experienced subjects.

OBJECTIVES: Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naïve subjects with transmitted resistance. METHODS: In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at week 48 [confirmed virological response (CVR), non-virological failure (VF) censored]. Key secondary endpoints included assessments of changes from baseline to week 48 in viral load, immunological response, pharmacokinetics/pharmacodynamics, safety, tolerability, metabolic and bone markers and body fat. RESULTS: Forty-one of the 54 enrolled subjects completed the study. Adverse events (7%) and VF (7%) were the most common reasons for discontinuation. The week 48 CVR rate in the intent-to-treat (ITT) non-VF censored population was 89% (primary endpoint). Seven subjects experienced VF. Common adverse events were diarrhoea (15%), rash (15%) and upper respiratory tract infection (11%). Mild/moderate lipid elevations, minimal changes in limb fat distribution and bone mineral density and no clinically relevant changes in glucose metabolism were observed. CONCLUSIONS: Etravirine 400 mg and darunavir/ritonavir 800/100 mg as a two-drug once-daily regimen in treatment-experienced subjects or treatment-naïve subjects with transmitted resistance was virologically efficacious and well tolerated.

Efficacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection.

OBJECTIVE: A randomized, open-label, multicenter study to establish clinical equivalence (non-inferiority) of a regimen employing a lamivudine 150 mg/zidovudine 300 mg combination tablet, administered twice daily, plus a marketed protease inhibitor, compared with a conventional regimen of 150 mg lamivudine twice daily, 600 mg zidovudine daily, and a protease inhibitor, in antiretroviral-experienced patients infected with HIV-1. PATIENTS: Adults who were seropositive for HIV-1 infection with plasma HIV-1 RNA levels < 10000 copies/ml (Roche Amplicor polymerase chain reaction assay, lower limit of quantitation (LLOQ) 400 copies/ml) and CD4+ cell counts > or = 300 x 10(6)/l). All patients had been receiving the conventional lamivudine/zidovudine/protease inhibitor regimen for > or = 10 weeks immediately prior to the study. INTERVENTION: Patients were randomized to the conventional regimen (n = 113) or combination tablet regimen (n = 110) for 16 weeks. The primary study endpoint was treatment failure, defined as an increase in HIV-1 RNA > or = 0.5 log10 above baseline in patients with viral load > LLOQ at randomization and as HIV-1 RNA increasing to > or = 1250 copies/ml in patients with viral load < LLOQ at randomization. RESULTS: The combination tablet regimen was associated with a 3.5% greater success rate than the conventional regimen (96.4 versus 92.9%), with four and eight patients failing treatment due to increases in HIV-1 RNA levels, respectively. The lower limit of the associated confidence interval for the difference was -2.4%, which was well within the -10% margin predefined as clinically unimportant. This establishes the clinical equivalence (non-inferiority) of the combination tablet regimen to the conventional regimens regarding virologic response. The combination tablet and conventional regimens were similar with respect to percentage of patients maintaining HIV-1 RNA levels < LLOQ at the end of study or improving from baseline to undetectability (94 versus 91%; P= 0.063), overall incidence of drug-related adverse events (21 versus 19%) (P=0.868), and mean area under the curve for CD4+ cell counts [treatment difference, 5.9 cells (95% confidence interval, -15.8 to 27.6 x 10(6) cells/l)]. A self-reported adherence questionnaire indicated that patients in the combination tablet group were less likely to miss doses of nucleoside analogue medication at weeks 8 (P= 0.007) and 16 (P= 0.046). CONCLUSIONS: The combination lamivudine/zidovudine tablet/protease inhibitor regimen is clinically equivalent (non-inferior) to the conventional regimen with respect to virologic response and may offer adherence advantages.

Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial.

PURPOSE: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4 + T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and high-dose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL-2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). METHOD: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4 + T cell counts less than 300 cells/microL at screening and a stable HIV viral load received low-dose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). RESULTS: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/microL in the IL-2 group compared to 19.93 cells/microL in the control group (p <.001). Additionally, IL-2-treated patients experienced a statistically significant increase in the mean percentage of CD4 + T cells (3.52% increase) when compared to control patients (1.33% increase) (p <.001). The expanded CD4 + T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p <.001 for between-group difference). In addition, a higher proportion of IL-2-treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p =.08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. CONCLUSION: Daily, low-dose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells.

Laparoscopic-guided biopsy for diagnosis of hepatic candidiasis.

Histopathological evaluation of infected tissue is critical in the diagnosis of hepatic candidiasis since cultures are unreliable. Percutaneous techniques are inaccurate because lesions often are small and multifocal, and open biopsy is not always well-tolerated in acutely ill patients. The authors investigated the feasibility of laparoscopically guided biopsy in patients suspected of having hepatic candidiasis. Preliminary results suggest that laparoscopically guided biopsy is highly accurate and less invasive than open biopsy.

Spirochete-like organisms in the human gastrointestinal tract.

Spirochete-like organisms were first detected in human feces in 1884. In the century since that observation an appreciable amount of epidemiologic and morphologic information has been published; nevertheless, it is not known how many species of cultivable human intestinal spirochetes exist, nor is the role of these organisms in health and disease known. Recent advances in microbiologic techniques, coupled with the recognition that the rate of carriage of such spirochetes in certain populations is approximately 30%-40%, should provide the impetus for careful scientific study of these organisms and of their importance-if any-to human health.

Disseminated infection caused by urease-negative Cryptococcus neoformans.

We report a case of fungemia and disseminated disease caused by a urease-negative strain of Cryptococcus neoformans in a patient with the acquired immune deficiency syndrome. Except for failure to hydrolyze urea, the microbiological characteristics of the isolate were typical of C. neoformans. Laboratory specialists should be aware of the occurrence of atypical strains of C. neoformans, particularly those recovered from patients with the acquired immune deficiency syndrome.

Ciprofloxacin for eradication of methicillin-resistant Staphylococcus aureus colonization.

Ciprofloxacin (750 mg orally twice a day) was used to treat 22 episodes of methicillin-resistant Staphylococcus aureus (MRSA) colonization among 20 patients. Most patients had serious, progressive underlying medical diseases and had multiple sites of colonization. Eleven had previously received parenteral vancomycin therapy. Duration of ciprofloxacin therapy was from seven to 28 days. Therapy was discontinued in eight patients because of minor adverse reactions (two patients) or serious events attributed to underlying diseases (six patients). These serious events included seizures in two patients with known seizure disorders. Of the remaining 14 courses of therapy, 11 (79 percent) were associated with eradication of MRSA colonization. For the 18 patients who received at least two weeks of therapy, results of cultures from 47 of the 56 colonized sites became negative. Recolonization with MRSA occurred in four patients within one month. Increased resistance to ciprofloxacin was observed in seven of the 22 treatment episodes; this was associated with treatment failure in three patients and successful therapy in one patient; therapy was discontinued for other reasons in three patients. For comparison, medical records of 31 patients whose clinical specimens revealed MRSA but who did not receive ciprofloxacin were reviewed. MRSA colonization (as opposed to infection) was not eradicated in any patient who received only a single drug or no specific therapy directed against MRSA; four of seven patients given combination therapy had colonization eradicated. Although there is the potential for increased resistance, ciprofloxacin is an important new option that can be used as a single agent for eradication of MRSA colonization. Additional study is needed to define the optimum use of ciprofloxacin as a single agent and in combination therapy for MRSA colonization and infection.

Failure of rapid agglutination methods to detect oxacillin-resistant Staphylococcus aureus.

Although a latex agglutination test (StaphAurex) and a hemagglutination test (Staphyloslide) correctly identified all strains of Staphylococcus aureus that were susceptible or had intermediate susceptibility to oxacillin, 17 of 73 (23%) and 18 of 73 (25%) strains of oxacillin-resistant S. aureus were not identified by StaphAurex and Staphyloslide, respectively. All strains not detected were resistant to trimethoprim-sulfamethoxazole and rifampin.

Comparison of culture, cytotoxicity assays, and enzyme-linked immunosorbent assay for toxin A and toxin B in the diagnosis of Clostridium difficile-related enteric disease.

Clostridium difficile culture, test tube, and microtiter cytotoxicity assays, and enzyme-linked immunosorbent assays (ELISAs) for toxin A and toxin B, were simultaneously performed on 113 fresh diarrheal stool specimens randomly selected from those submitted to our clinical laboratory for routine C. difficile testing. The performance of these tests in diagnosing C. difficile-related enteric disease (CDRED) was based on a clinical assessment of the likelihood of CDRED as determined by a systematic review of case histories blinded from the test results. Among 61 antibiotic recipients, both the microtiter cytotoxicity assay and the toxin A ELISA were highly specific for CDRED (95% and 100%, respectively). Specificities for the other procedures were much lower (tube cytotoxicity assay, 79%; culture, 74%; and toxin B ELISA, 56%). The high sensitivities of the culture (89%) and toxin B ELISA (83%) were somewhat negated by their low specificities. The only test that was both specific and had acceptable sensitivity (78%) was the microtiter cytotoxicity assay. This study indicates that ELISAs for detection of C. difficile toxins are not as reliable as the cytotoxicity assay in the laboratory diagnosis of CDRED, and that clinical correlation is essential in the evaluation of any new test for CDRED.

Intravenous catheter-associated fungemia due to Candida rugosa.

We report a case of intravenous catheter-associated fungemia caused by Candida rugosa; this is the first report of such an infection in a human. Multiple cultures of blood taken over a 24-h period and of the intravenous catheter tip were positive for this unusual isolate. The patient was treated with intravenous amphotericin B and made an uneventful recovery. Intravenous cannulae and other intravascular devices are well recognized as potential sites of intravascular infection by a variety of microorganisms, including several Candida species; however, fungemia caused by C. rugosa has not been reported.