A member of the major human cytochrome P450 superfamily of hemoproteins, CYP3A4/5, converts cholesterol into 4β-hydroxycholesterol. We studied plasma 4β-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 4β-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.

Background: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. Methods: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. Results: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. Conclusions: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

BACKGROUND:We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. METHODS:We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. RESULTS:During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/microL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. CONCLUSION:The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.

BACKGROUND Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis. METHODS We determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002. RESULTS In Europe, 1 of 10 antiretroviral-naive patients carried viruses with > or = 1 drug-resistance mutation. Recently infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs. 8.7%; P=.006). Non-B viruses (30%) less frequently carried resistance mutations than did subtype B viruses (4.8% vs. 12.9%; P<.01). Baseline resistance increased over time in newly diagnosed cases of non-B infection: from 2.0% (1/49) in 1996-1998 to 8.2% (16/194) in 2000-2001. CONCLUSIONS Drug-resistant variants are frequently present in both recently and chronically infected therapy-naive patients. Drug-resistant variants are most commonly seen in patients infected with subtype B virus, probably because of longer exposure of these viruses to drugs. However, an increase in baseline resistance in non-B viruses is observed. These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated.

D.A.M.C. van de Vijver, A.M.J. Wensing, G. Angarano, B. Asjo, C. Balotta5, E. Boeri, R. Camacho, M-L. Chaix, D. Costagliola, E.L.M. Op de Coul, A. de Luca, I. Maljkovic, C. de Mendoza, I. Derdelinckx, Z. Grossman, O. Hamouda, A. Hatzakis, I.M. Hoepelman, R. Hemmer A. Horban, K. Korn, C. Kucherer, T. Leitner, C. Loveday, E. MacRae, L. Meyer, C. Nielsen, V. Ormaasen, L. Perrin, D. Paraskevis, E. Puchhammer-Stockl, L. Ruiz, .M Salminen, J.C.C. Schmit, F. Schneider, R. Schuurman, V. Soriano, G. Stanczak, M. Stanojevic, A-M. Vandamme, K. Van Laethem, M. Violin, K. Wilbe, S. Yerly, M. Zazzi and C.A.B. Boucher on behalf of the SPREAD Programme.

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.

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.

The aim of this study was to evaluate the prognostic value of changes in CD4 counts and human immunodeficiency virus (HIV) RNA following 6 months of highly active antiretroviral therapy (HAART) in chronic HIV-1 infection. 148 treatment-naïve patients treated with 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs)+at least 1 protease inhibitor or non-NRTI for at least 180 d were included. Mean follow-up time after 6 months on HAART was 758 d. The patients were divided into 2 groups based on the increase in CD4 count (ΔCD4) from therapy initiation: groups A (n=37, ΔCD4<0.052×109/l) and B (n=111, ΔCD4≥0.052×109/l). Patients were also stratified according to achievement of HIV RNA<400 copies/ml (n=122) or ≥400 copies/ml (n=26). Endpoints were the occurrence of subsequent HIV-related disease (CDC category B or C) or death after 6 months on HAART. Subjects in group A had an increased risk of HIV-related disease compared with group B when adjusted for CD4 count at initiation of therapy [adjusted risk ratio (RR) 2.62, 95% confidence interval (95% CI) 1.07-6.40]. Viral load≥copies/ml versus reaching viral suppression<400 copies/ml was associated with an increased risk of HIV-related disease only in patients with ΔCD4<0.052×109/l (RR 4.20, 95% CI 1.05-16.9). Thus, this study indicates that patients with no or a small increase in CD4 counts after 6 months of HAART and low CD4 levels at initiation of therapy have an increased risk of HIV-related disease.

This study prospectively assessed the impact of treatment modality, virus load, and CD4 cell count of <50 cells/mm(3) on human immunodeficiency virus disease progression. The incidence rate of new AIDS disease or death was 54.8 (95% confidence interval, 48.7-59.9) per 100 person-years of follow-up. Independent predictors related to progression were latest CD4 cell count (relative risk [RR], 0.84/10 mm(3) higher; P < .0001), latest hemoglobin level (RR, P 0.79/ g/L higher; P < .0001), Pneumocystis carinii pneumonia prophylaxis (RR, 0.49; P <.0001), latest body mass index (RR, 0.93/kg/m(2) higher; P = .002), latest virus load (RR, 1.11/ log(10) higher; P = .03), and intensity of treatment (RR, 1.82, P = .004; RR 2.27, P < .0001;RR 2.46, P = .0001; RR 2.33 P < .0006; 5.10, P < .0001, respectively, for 4, 3, 2, 1, or no drugs vs. >= 5 drugs). Although reverse causality cannot be excluded, more intense antiviral treatment appears to decrease the risk of progression in immunocompromised patients.

The study objective was to identify optimal starting criteria regarding levels of CD4 cells and human immunodeficiency virus (HIV) RNA at initiation of highly active antiretroviral therapy (HAART) in chronically HIV-infected people. All 162 treatment-naive patients in the centre who were treated for at least 180 d with 2 nucleoside reverse transcriptase inhibitors plus at least 1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor were included. The patients were stratified according to their levels of CD4 cells and HIV RNA at initiation of therapy. Baseline CD4 groups were: group 1: CD4 < 0.1 x 10(9)/l; group 2: CD4 > or = 0.1 and < 0.2 x 10(9)/l; group 3: CD4 > or = 0.2 and < 0.35 x 10(9)/l; and group 4: CD4 > or = 0.35 x 10(9)/l. Two patients died and 38 developed an HIV-related disease (Centers for Disease Control category B or C) during the study. The prevalence of HIV-related disease before HAART was significantly increased in groups 1 and 2 compared with groups 3 and 4. The level of HIV RNA was not associated with HIV-related disease either before or after treatment initiation. Subjects in group 1 had an increased risk of HIV-related disease after treatment initiation both in univariate Cox analysis and after adjustment for HIV RNA, gender, mode of transmission and age, compared with group 2 [adjusted risk ratio with 95% confidence interval: 3.76 (1.48-9.61)], group 3 [5.90 (2.07-16.95)] and group 4 [5.05 (1.96-12.90)]. The association between CD4 count and morbidity appeared to be particularly strong for older subjects. In conclusion, this study suggests that in chronically HIV-infected individuals, in most cases HAART can be withheld until the CD4 cell count falls towards 0.2 x 10(9)/l.

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.

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.

BACKGROUNDHIV-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 METHODSWe present a review on this topic based on relevant literature and clinical experience.RESULTSTreatment 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.INTERPRETATIONTreatment 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.

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.

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.