William Cameron

Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

OBJECTIVE To evaluate the safety and antiretroviral activity of ritonavir (Norvir) and saquinavir (Invirase) combination therapy in patients with HIV infection. DESIGN A multicenter, randomized, open-label clinical trial. SETTING Seven HIV research units in the USA and Canada. PATIENTS A group of 141 adults with HIV infection, CD4 T lymphocyte counts of 100-500 x 10(6) cells/l, whether treated previously or not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibitor drug therapy. INTERVENTIONS After discontinuation of prior therapy for 2 weeks, group I patients were randomized to receive either combination (A) ritonavir 400 mg and saquinavir 400 mg twice daily or (B) ritonavir 600 mg and saquinavir 400 mg twice daily. After an initial safety assessment of group I patients, group II patients were randomized to receive either (C) ritonavir 400 mg and saquinavir 400 mg three times daily or (D) ritonavir 600 mg and saquinavir 600 mg twice daily. Investigators were allowed to add up to two reverse transcriptase inhibitors (including at least one with which the patient had not been previously treated) to a patients regimen after week 12 for failure to achieve or maintain an HIV RNA level < or = 200 copies/ml documented on two consecutive occasions. MEASUREMENTS Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measured at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examinations, and the monitoring of routine laboratory tests. RESULTS The 48 weeks of study treatment was completed by 75% (106/141) of the patients. Over 80% of the patients on treatment at week 48 had an HIV RNA level < or = 200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasma HIV RNA levels was similar for all treatment arms (mean areas under the curve minus baseline through 48 weeks were-1.9, -2.0, -1.6, -1.8 log10 copies/ml in ritonavir-saquinavir 400-400 mg twice daily, 600-400 mg twice daily, 400-400 mg three times daily, and 600-600 mg twice daily, respectively). Median CD4 T-lymphocyte count rose by 128 x 10(6) cells/l from baseline, with an interquartile range (IQR) of 82-221 x 10(6) cells/l. The most common adverse events were diarrhea, circumoral paresthesia, asthenia, and nausea. Reversible elevation of serum transaminases (> 5 x upper limit of normal) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline hepatitis B surface antigen positivity, or hepatitis C antibody positivity (relative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or severe elevations in liver function tests occurred in patients treated with ritonavir-saquinavir 600-600 mg twice daily. CONCLUSIONS Ritonavir 400 mg combined with saquinavir 400 mg twice daily with the selective addition of reverse transcriptase inhibitors was the best-tolerated regimen of four dose-ranging regimens and was equally as active as the higher dose combinations in HIV-positive patients without previous protease inhibitor treatment.

Expression of IL-10, IL-4 and interferon-gamma in unstimulated and mitogen-stimulated peripheral blood lymphocytes from HIV-seropositive patients

Infection of immune cells with HIV induces dysregulation of cytokines which may play a vital role in HIV pathogenesis. We analysed the expression of T helper type I (Th1) (interferon‐gamma (IFN‐γ)) and Th2 (IL‐4, IL‐10) type cytokines in peripheral blood lymphocytes (PBL) from HIV patients. The semiquantitative reverse transcriptase polymerase chain reaction (RT‐PCR) analysis revealed that IFN‐γ mRNA in unstimulated PBL was significantly decreased and IL‐10 mRNA was significantly upregulated in patients with < 400 CD4+ T cells/mm3 (n= 30) as compared to patients with > 400 CD4+ T cells/mm3 (n= 6) and normal controls (n= 16). In addition. IL‐10 mRNA levels were inversely associated with IFN‐γ expression. Similar results were obtained by measuring IL‐10 production in the supernatants of PBL cultured in vitro without stimulation by employing an enzyme immunosorbent assay (ELISA). However, the levels of IL‐4 and IFN‐7 produced by unstimulated PBL were undetectable by ELISA. Mitogen stimulation of PBL revealed two groups of HIV individuals based on IL‐10 production. PBL from one set of individuals produced low levels of IL‐10 (low IL‐10 producers) whereas the other group produced IL‐10 comparable lo that of normal controls (IL‐10 producers). Production of IL‐4 was significantly reduced in HIV+ individuals with<400 CD4+ T cells/mm3 as compared to the normal controls. However, ability to produce IFN‐γ by mitogen‐stimulated total PBL and CD4+ purified cells was not impaired in HIV+ individuals. These results suggest that unstimulaied and mitogen‐stimulated PBL of HIV+ individuals exhibit dysregulation of Th2 type cytokines which may play a role in HIV immunopathogenesis.

Differential production of IL-10 by T cells and monocytes of HIV-infected individuals: association of IL-10 production with CD28-mediated immune responsiveness

Immune unresponsiveness in HIV‐1 infection can result from impaired signals delivered by the costimulatory CD28‐B7 pathway and the altered production of immunoregulatory cytokines, in particular IL‐10, whose production is altered in HIV‐1 infection. In this study we investigate IL‐10 regulation in T cells and monocytes from HIV+ individuals, and its association with CD28‐mediated T cell proliferation. IL‐10 production as analysed in T cell‐ and monocyte‐depleted peripheral blood mononuclear cells (PBMC), and by intracellular staining at the single‐cell level, reveals a defect in IL‐10 production by CD4+ and CD8+ T cells, whereas monocytes constitute the major IL‐10‐producing cell type. To investigate the impact of IL‐10 on immune responsiveness, CD28‐mediated proliferative responses in HIV+ individuals were correlated with PHA‐induced IL‐10 production. CD4+ T cells expressed CD28, yet exhibited markedly reduced CD28‐mediated cell proliferation. This CD28‐mediated CD4+ T cell proliferation was found to be inversely associated with the levels of PHA‐induced IL‐10 production and could be restored, at least in part, by anti‐IL‐10 antibodies. These results suggest that IL‐10 production is differentially regulated in T cells and monocytes of HIV+ individuals, and that IL‐10 may have a role in inducing immune unresponsiveness by modulating the CD28‐B7 pathway.

Nef Protein of Human Immunodeficiency Virus and Lipopolysaccharide Induce Expression of CD14 on Human Monocytes through Differential Utilization of Interleukin-10

ABSTRACT We investigated the expression of membrane-bound CD14 (mCD14) on monocytes and soluble CD14 (sCD14) released into the culture supernatants of peripheral blood lymphocytes (PBMC) from human immunodeficiency virus (HIV)-infected individuals. Monocytes from HIV-positive individuals exhibited both enhanced mCD14 expression and sCD14 production in the PBMC culture supernatants compared to the levels of mCD14 and sCD14 in HIV-negative individuals. This enhanced mCD14 expression and sCD14 production in HIV-infected individuals may be due to the effects of cytokines, the bacterial product lipopolysaccharide (LPS), and/or the HIV regulatory antigens Tat and Nef. Interleukin-10 (IL-10), an immunoregulatory cytokine, as well as LPS enhanced mCD14 expression and the release of sCD14 in the culture supernatants. HIV-Nef, unlike Tat, enhanced mCD14 expression on monocytes but did not induce the release of sCD14 into the culture supernatants. Studies conducted to investigate the mechanism underlying HIV-Nef-induced mCD14 expression revealed that HIV-Nef upregulated mCD14 expression via a mechanism that does not involve endogenously produced IL-10. In contrast, LPS upregulated the expression of mCD14 and increased the release of sCD14 via a mechanism that involves, at least in part, endogenously produced IL-10. Furthermore, dexamethasone, an anti-inflammatory and immunosuppressive agent, inhibited HIV-Nef-induced CD14 expression in an IL-10-independent manner. In contrast, dexamethasone inhibited IL-10-dependent LPS-induced CD14 expression by interfering with IL-10-induced signals but not by blocking IL-10 production. These results suggest that HIV-Nef and IL-10 constitute biologically important modulators of CD14 expression which may influence immunobiological responses to bacterial infections in HIV disease.

Prospective, Randomized Comparison of Intravenous and Oral Ciprofloxacin with Intravenous Ceftazidime in the Treatment of Nosocomial Pneumonia

OBJECTIVE To compare the efficacy of intravenous and oral ciprofloxacin and intravenous ceftazidime in the treatment of nosocomial pneumonia. DESIGN Randomized, nonblinded, multicentre comparative trial. SETTING Seven Canadian university hospitals. POPULATION Adult patients with moderate to severe pneumonia developing 72 h or longer after hospitalization. METHODS After informed consent was obtained, patients were randomized to receive intravenous ciprofloxacin 300 mg every 12 h or ceftazidime 2 g every 8 h. After three days, patients in the ciprofloxacin arm could be switched to oral ciprofloxacin, 750 mg every 12 h. Concomitant clindamycin was allowed for three days in patients with syndromes consistent with Gram-positive or anaerobic infection. Erythromycin could be used if cultures revealed no pathogen. RESULTS A total of 149 patients were enrolled, of whom 124 were eligible for efficacy analysis. Of 119 pathogens identified in 87 patients, 84 were Gram-negative, and 35 Gram-positive. The mean duration of ciprofloxacin therapy was 12.1 days, of which 9.2 days were given intravenously. Ceftazidime was given for a mean of 9.8 days. There was eradication or reduction of pathogens in 75.7% of ciprofloxacin patients and 70.6% of the ceftazidime group. Clinical resolution or improvement occurred in 87.1% of ciprofloxacin recipients and 87.3% of the ceftazidime group. Eight ciprofloxacin and six ceftazidime patients died. Overall outcomes were considered to be successful in 85.2% of ciprofloxacin patients and 87.1% of ceftazidime recipients. Adverse events were mild. CONCLUSIONS There were similar efficacy and safety of intravenous and oral ciprofloxacin and intravenous ceftazidime in the treatment of patients with hospital-acquired pneumonia. Physicians were reluctant to use oral therapy in patients.

Assessment of stigma in patients with cystic fibrosis

BackgroundResearch that explores stigma in Cystic Fibrosis (CF) is limited. Productive cough, repeated lung infections, and periods of serious illness requiring hospitalizations are among common symptoms of CF. These symptoms may cause a negative perception by others. We developed a CF-specific Stigma Scale and tested its psychometric properties.MethodsWe conducted a focus group with 11 participants including adult patients with CF (n = 5) and their informal caregivers (n = 6). The thematic content of the focus group was analyzed to find key themes. We developed a CF-specific Stigma Scale and assessed its psychometric properties in a 3-month prospective cohort study of adult CF outpatients (n = 45).ResultsStigma emerged as consistent concern for people living and caring for those with CF, affecting both patients’ lives and health through the focus group. Using the newly developed CF Stigma scale, the mean baseline score was 16.6 (SD = 4.5, Range = 10-25). The CF Stigma Scale demonstrated robust psychometric properties: 1) Internal consistency: α = 0.79; 2) Mean inter-item correlation: 0.30 with good test-retest reliability; 3) Convergent validity: Positive associations with depression, severity of CF symptoms and anxiety; negative associations with validated quality of life scores were observed.ConclusionsStigma is measurable and significantly impacts the lives of CF patients. Further research should investigate the role of stigma in patients living with CF.

Pharmacokinetics of simultaneously administered zidovudine and didanosine in HIV-seropositive male patients.

Our objective was to determine whether a pharmacokinetic interaction exists between zidovudine and didanosine when they are coadministered. This was designed as a randomized, three-period, three-treatment, six-sequence, crossover study with a 1-week washout period between treatments. The patients were six men infected with human immunodeficiency virus who were asymptomatic. On three separate occasions, patients received zidovudine alone (200 mg every 8 h) for 3 days, didanosine alone (200 mg every 12 h) for 3 days, or zidovudine and didanosine for 3 days. On the fourth day, each patient received the final dose of each regimen, and blood and urine were serially collected for 8 h. Pharmacokinetic parameters were assessed for zidovudine, its glucuronide metabolite (GZDV), and didanosine. Coadministration of zidovudine had no significant effect on didanosine pharmacokinetic parameters (< 12% difference between treatment means, p > 0.1). Coadministration of didanosine did not significantly alter zidovudine pharmacokinetic parameters but did cause statistically significant increases in the renal and apparent formation clearances of GZDV (18.5% and 30.5% difference between the treatment means, respectively, p < 0.025). Therapeutic doses of zidovudine did not alter didanosine pharmacokinetic parameters. Coadministration of didanosine did not affect zidovudine parameters but did cause small alterations in GZDV pharmacokinetic values. These changes are unlikely to be clinically significant.

Development and psychometric validation of a cystic fibrosis knowledge scale

Well‐developed and validated measures of cystic fibrosis (CF) knowledge are scarce. The purpose of the present study is to develop and validate a CF knowledge scale that is brief, easy to use, self‐administered and demonstrates clinical utility.

When infections collide—gummatous syphilis in an HIV-infected individual

Syphilis and HIV are both transmitted sexually and have emerged as important co-pathogens with reciprocal augmentation in transmission and disease progression. HIV-positive patients tend to experience more aggressive symptomatology due to syphilis and are at greater risk of developing neurological disease. Similarly, standard therapy for syphilis may be inadequate in HIV-positive individual suggesting intensified treatment regimens may be required along with close follow-up. We report here the case of a 50-year-old HIV-positive male presenting with an unusual constellation of neurological findings. Although he had been treated appropriately 10 years previously for primary syphilis, investigations revealed multiple current intracranial gummas. Treatment with high-dose intravenous penicillin G resulted in clinical and radiographic resolution. Given the broad differential for HIV-positive patients presenting with neurological symptoms, the clinician must maintain a high index of suspicion for syphilis known for its varied and at times unusual manifestations. Further, prior treatment of syphilis does not ensure cure and so syphilis must be considered irrespective of treatment history.

Subcutaneous Immunoglobulin Therapy in the Chronic Management of Myasthenia Gravis: A Retrospective Cohort Study

Background Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a practical and effective option in chronic management of MG. We analyzed clinical outcomes and patient satisfaction in nine cases of chronic disabling MG who were either transitioned to, or started de novo on SCIg. Methods and Findings This was a retrospective cohort study for the period of 2015–2016, with a mean follow-up period of 6.8 months after initiation of SCIg. All patients with MG treated with SCIg at the Ottawa Hospital, a large Canadian tertiary hospital with subspecialty expertise in neuromuscular disorders were included, regardless of MG severity, clinical subtype and antibody status. The primary outcome was MG disease activity after SCIg initiation. This outcome was measured by 1) the Myasthenia Gravis Foundation of America (MGFA) clinical classification, and 2) subjective scales of disease activity including the Myasthenia Gravis activities of daily living profile (MG-ADL), Myasthenia Gravis Quality-of-life (MG-QOL 15), Visual Analog (VA) satisfaction scale. We also assessed any requirement for emergency department visits or hospitalizations. Safety outcomes included any SCIg related complication. All patients were stable or improved for MGFA class after SCIg initiation. Statistically significant improvements were documented in the MG-ADL, MG-QOL and VAS scales. There were no exacerbations after switching therapy and no severe SCIg related complications. Conclusions SCIg may be a beneficial therapy in the chronic management of MG, with favorable clinical outcome and patient satisfaction results.