CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4beta-hydroxycholesterol levels.

OBJECTIVE AND METHODS: A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4beta-hydroxycholesterol. We studied plasma 4beta-hydroxycholesterol levels prior to and 4 weeks after initiating antiretroviral therapy that included efavirenz, ritonavir-boosted atazanavir or ritonavir-boosted lopinavir with the aim of exploring the usefulness of plasma 4beta-hydroxycholesterol levels as an endogenous biomarker of CYP3A activity. Efavirenz is an inducer of CYP3A, whereas the ritonavir-boosted regimens are net inhibitors of CYP3A. RESULTS: In patients treated with efavirenz, the median plasma 4beta-hydroxycholesterol level increased by 46 ng/mL (p = 0.004; n = 11). In contrast, patients given ritonavir-boosted atazanavir showed a median decrease in plasma 4beta-hydroxycholesterol of -9.4 ng/mL (p = 0.0003; n = 22), and those given ritonavir-boosted lopinavir showed a median change from baseline of -5.8 ng/mL (p = 0.38; n = 19). There were significant between-group differences in the effects of antiretroviral treatment on plasma 4beta-hydroxycholesterol levels (p < 0.0001). CONCLUSION: Changes in plasma 4beta-hydroxycholesterol following the initiation of efavirenz- or atazanavir/ritonavir-based antiretroviral therapy reflected the respective net increase and decrease of CYP3A activity of these regimens. The plasma 4beta-hydroxycholesterol level did not indicate a net CYP3A inhibition in the lopinavir/ritonavir arm, possibly because of concomitant enzyme induction.

An algorithm-based genotypic resistance score is associated with clinical outcome in HIV-1-infected adults on antiretroviral therapy.

OBJECTIVES: The aim of this study was to evaluate the association between genotypic drug resistance and the occurrence of HIV-related diseases and death in HIV-1-infected adults on antiretroviral therapy. METHODS: We performed an observational study on patients from an out-patient clinic in a university hospital. Genotypic drug resistance analysis after virological treatment failure was performed in 141 patients receiving two or more antiretroviral drugs. All patients had follow up of at least 6 months after the resistance test. An algorithm was developed to estimate the level of genotypic drug resistance and to assign an actual resistance score (ARS) for the drugs prescribed to each patient. The patient population was divided into quartiles according to patients' ARS values. Our endpoint was the risk of developing an HIV-related disease [Centers for Disease Control and Prevention (CDC) category B or C] during the period starting 6 months prior to and ending 6 months after the genotypic resistance test, or death during the 6 months following the resistance test. RESULTS: There was a significant association between the level of resistance to the drugs prescribed (ARS) and our clinical endpoint: the odds ratio for an endpoint (with 95% confidence interval) was 3.20 (1.28-7.99), adjusted for CD4 cell count and HIV RNA, in patients in the highest ARS quartile compared with patients in the other three quartiles. CONCLUSIONS: Our study indicates that patients with high-level genotypic drug resistance are at increased risk of developing an HIV-related disease. This association could not be explained by differences in CD4 cell count or HIV RNA levels.

Immunoglobulin levels amongst persons with and without human immunodeficiency virus type 1 infection in Uganda and Norway.

CD4+-cell count and viral load monitoring are expensive and unavailable to most human immunodeficiency virus (HIV)-infected people in Africa. In an attempt to evaluate alternative methods for monitoring antiretroviral (ARV) therapy, we measured concentrations of immunoglobulin (Ig)A, IgM, IgG and IgG1 amongst adults with and without HIV in Uganda and Norway. We adjusted for disease severity by stratifying HIV-positive subjects on CD4+-cell counts above and below 200 cells/ micro l. Median serum levels of IgG, IgG1 and IgA were significantly higher in HIV-positive persons compared with HIV-negative persons in both countries (P < 0.001 and P = 0.018 for IgA in Ugandan patients). Levels of IgA in Ugandan HIV-negative subjects were significantly lower than those in HIV-positive subjects with low CD4+ compared with those with high CD4+-cell counts (P < 0.001 and P = 0.069, respectively). IgM levels were different between the HIV-negative and the two HIV-positive groups in Norway (P < 0.001). The mean levels of IgM, IgG and IgG1 in HIV-negative and -positive African subjects were generally higher than those in comparable groups of Western subjects. Our results verify that levels of IgA, IgG and IgG1 vary between HIV-negative and -positive individuals in both study populations. Their determination may be useful in monitoring both disease progression and response to ARV therapy.

[Two cases of pneumococcal pericarditis]. / To tilfeller av pneumokokkperikarditt.

BACKGROUND: Bacterial pericarditis is often overlooked, partly because symptoms and signs associated with pericarditis are frequently missing, but also because of the rarity of the disease. MATERIAL AND METHODS: Two cases of pneumococcal pericarditis treated at Ullevaal University Hospital are presented. RESULTS: Pneumococcal pericarditis is a rare, but serious complication to infections like pneumonia, pleural empyema, and septicaemia. Patients with an infectious disease who develop signs of elevated central venous pressure, enlarged cardiac silhouette on chest x-ray, or severe hypotension should have an echocardiography performed. If pericardial fluid is present, a diagnostic pericardiocentesis should be considered. INTERPRETATION: Treatment consists of drainage and antibiotics. Pericardiocentesis and subxiphoid catheter drains may be inadequate because of fibrin precipitation resulting in organization of the fluid. In these cases surgical intervention has traditionally been recommended, but intrapericardial fibrinolysis could be an alternative.

[Tick-borne encephalitis in Norway]. / Flåttbåren encefalitt i Norge.

BACKGROUND: Tick-borne encephalitis is caused by a virus that is transmitted to man by tick-bite. The virus is found in central and eastern parts of Europe and also in Sweden. MATERIAL AND METHODS: We report the first two cases of tick-borne encephalitis resulting from transmission of virus in Norway. RESULTS: Both patients had been to the island of Tromøy on the south coast of Norway. The course of the disease was very different in the two patients. One patient had significant neurological dysfunction. The other patient had intense headache, but no motor dysfunction. Both patients had reduced general health and fever, and leukocytosis and increased protein was found in the spinal fluid. The incubation period is most often 1 to 2 weeks. The disease may have a bi-phasic course with initial fever, headache and muscle pain. One week later symptoms of encephalitis follow. Subclinical infection is common, especially in children. One third of patients get permanent sequelae after encephalitis. Diagnosis is made by demonstration of antibodies in serum. Treatment is symptomatic. INTERPRETATION: These two patients indicate that there may be a reservoir of TBE virus in Norway.

[Antiviral therapy of HIV infection in adults]. / Antiviral behandling av kronisk HIV-infeksjon hos voksne.

BACKGROUND: Great progress has been made in antiviral treatment of HIV disease over the last few years. MATERIAL AND METHODS: The paper is based on relevant literature and our own experience in the largest HIV clinic in Norway. RESULTS AND INTERPRETATION: Generally speaking, therapy with at least three active drugs is necessary in order to obtain maximum viral suppression. It is not established what constitutes the best starting-point for therapy, or what combination of drugs is the most efficacious. Treatment should be initiated before clinical immunodeficiency develops. All patients with CD4 counts < or = 0.2 x 10(9)/l should be offered treatment. The initial regimen should be either two nucleoside-analogues and one or two protease inhibitors, or two nucleoside-analogues and efavirenz. In order to avoid resistance and treatment failure, the patient should be thoroughly informed before and during treatment about the importance of good compliance.

[Tuberculosis among HIV-infected persons in Norway]. / Tuberkulose hos HIV-smittede i Norge.

BACKGROUND: HIV-infected persons have a considerably higher risk of developing active tuberculosis than immunocompetent individuals. Tuberculosis is the only opportunistic infection among HIV-infected persons that presents a potential health risk to the general population. MATERIAL AND METHODS: We present a review on this topic based on relevant literature and clinical experience. RESULTS: Treatment options are limited because of interactions between rifamycins and protease inhibitors and non-nucleoside analogues. When concomitant therapy against HIV infection and tuberculosis is indicated, we suggest a first-line regimen of rifabutin combined with either indinavir or nelfinavir. For patients without severe immunodeficiency, anti-retroviral therapy can be postponed until the end of the initial phase of the anti-tuberculosis treatment. INTERPRETATION: Treatment of concurrent HIV infection and tuberculosis is complex and may involve multiple drug regimens. Treating the latent infection could in many cases prevent active tuberculosis. All HIV-infected persons should be evaluated with respect to active tuberculosis and latent infection.

[Practical approach to otitis media with methicillin-resistant yellow Staphylococci]. / Praktisk håndtering av otitis media med meticillinresistente gule stafylokokker.

Methicillin-resistant Staphylococcus aureus (MRSA) are multiresistant bacteria, known to cause nosocomial infections. We present a report on a two and a half year-old, recently adopted, child, who suffered from otitis media with discharge. The child was treated with penicillin in Norway without success. Culture revealed methicillin-resistant S aureus. Methicillin-resistant S aureus were also found in the noses of the adoptive parents. After a second unsuccessful course of antibiotics the child was admitted to the Ear, nose, and throat department and was subsequently treated with intravenous vancomycin, mastoidectomy and eradication of the nasal methicillin-resistant S aureus carriage. The admittance to the Ear, nose, and throat department was carefully planned. All departments concerned were thoroughly briefed. The patient was given vancomycin intravenously for 18 days, partly as an out-patient. Subsequent control cultures from the patient and the adoptive parents have all been negative. No one dealing with the patient has been infected. The case illustrates the importance of thorough planning and co-operation between different departments.