Publications by authors named "Mona Holberg-Petersen"

21 Publications

  • Page 1 of 1

Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.

Proc Natl Acad Sci U S A 2020 10 17;117(40):25018-25025. Epub 2020 Sep 17.

Institute of Clinical Medicine, University of Oslo, 0315 Oslo, Norway.

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO/FiO ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure ( = 0.008 and = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin ( = 0.64, < 0.001; = 0.69, < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
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http://dx.doi.org/10.1073/pnas.2010540117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547220PMC
October 2020

Fatal primary amoebic meningoencephalitis in a Norwegian tourist returning from Thailand.

JMM Case Rep 2016 Jun 25;3(3):e005042. Epub 2016 Jun 25.

Department of Infectious Diseases, Oslo University Hospital - Ullevaal, Oslo, Norway.

Introduction: Primary amoebic meningoencephalitis (PAM) is a rare disease caused by the free-living amoeba . Infection occurs by insufflation of water containing amoebae into the nasal cavity, and is usually associated with bathing in freshwater. Nasal irrigation is a more rarely reported route of infection.

Case Presentation: A fatal case of PAM in a previously healthy Norwegian woman, acquired during a holiday trip to Thailand, is described. Clinical findings were consistent with rapidly progressing meningoencephalitis. The cause of infection was discovered by chance, owing to the unexpected detection of DNA by a PCR assay targeting fungi. A conclusive diagnosis was established based on sequencing of DNA from brain biopsies, supported by histopathological findings. Nasal irrigation using contaminated tap water is suspected as the source of infection.

Conclusion: The clinical presentation of PAM is very similar to severe bacterial meningitis. This case is a reminder that when standard investigations fail to identify a cause of infection in severe meningoencephalitis, it is of crucial importance to continue a broad search for a conclusive diagnosis. PAM should be considered as a diagnosis in patients with symptoms of severe meningoencephalitis returning from endemic areas.
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http://dx.doi.org/10.1099/jmmcr.0.005042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330229PMC
June 2016

High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway, autumn 2014.

Influenza Other Respir Viruses 2015 Mar 23;9(2):59-63. Epub 2014 Dec 23.

Department of Virology, Norwegian Institute of Public Health, Oslo, Norway.

Objectives: An unexpectedly high proportion of children were admitted for severe respiratory infections at the Oslo University Hospital, Ullevål, Norway, during September and October, 2014. In light of the ongoing outbreak of enterovirus-D68 (EV-D68) in North America a real-time RT-PCR for screening of enterovirus and enterovirus D68 was established.

Design: We developed a duplex real-time RT-PCR for rapid screening of enterovirus D68. The method target the 5' non-translated region (NTR) of the HEV genome at a location generally used for enterovirus detection.

Sample: Nasopharyngeal samples (n = 354), from children <15 years of age, received for respiratory virus analysis in OUH during September 1st and October 31nd, 2014, were tested for enterovirus and screened for enterovirus D68.

Main Outcome Measures And Results: The duplex real-time RT-PCR method was an efficient tool for rapid screening for EV-D68 in respiratory specimens. Enterovirus was detected in 66 (22%) of 303 pediatric nasopharyngeal samples collected from children hospitalised with acute respiratory infection within the two-month period. Out of these, 33 (50%) were EV-D68. EV-D68 was associated with acute flaccid paralysis in one child.

Conclusions: An unexpectedly high proportion of children admitted for severe respiratory infections at the Oslo University Hospital, Ullevål, Norway, were diagnosed with EV- D68 during September 1st and October 31nd, 2014. These results emphasise that greater vigilance is required throughout Europe as enteroviruses are cause of severe respiratory disease.
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http://dx.doi.org/10.1111/irv.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353317PMC
March 2015

Comparison of PCR and serotyping of Group B Streptococcus in pregnant women: the Oslo GBS-study.

J Microbiol Methods 2015 Jan 13;108:31-5. Epub 2014 Nov 13.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Streptococcus agalactiae (GBS) is a leading cause of invasive neonatal infection. Serotyping of GBS is important in following epidemiological trends and vaccine development. Capsular serotyping of GBS by latex agglutination has been the predominant typing method, but more recently capsular genotyping has been introduced as an alternative method. The purpose of this study was to compare the relative performance of these methods in a contemporary population of pregnant women. We typed isolates from an unselected population of 426 colonized women at delivery using latex agglutination and a combination of four PCR methods. Antibiotic resistance was tested in 449 isolates. Capsular genotyping gave a result in all except three of 426 isolates. Fifty-nine of 426 isolates could not be typed by latex agglutination. Agreement between serotyping and genotyping was shown in 303 (71.1%) of the isolates. 10.2% of the isolates were resistant to erythromycin, 9.6% to clindamycin, 76.6% to tetracycline and none to penicillin. In conclusion, a substantial proportion of the colonizing strains were non-typeable by serotyping, but typeable by genotyping. This suggests that a diagnostic genotyping strategy is preferable to serotyping of the GBS polysaccharide capsule in colonized, pregnant women.
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http://dx.doi.org/10.1016/j.mimet.2014.11.001DOI Listing
January 2015

Cytomegalovirus viremia in dried blood spots is associated with an increased risk of death in HIV-infected patients: a cohort study from rural Tanzania.

Int J Infect Dis 2012 Dec 30;16(12):e879-85. Epub 2012 Sep 30.

Department of Infectious Diseases, Oslo University Hospital, POB 4956 Nydalen, N-0424 Oslo, Norway.

Objectives: The objectives of the study were to assess the utility of dried blood spots (DBS) for the detection of cytomegalovirus (CMV) antibody and viremia in a resource-poor setting, to study the prevalence of CMV antibody and viremia in HIV-infected patients with access to antiretroviral therapy (ART) in Tanzania, and to relate CMV viremia to outcome.

Methods: DBS were prepared from 168 ART-naïve patients at baseline. Demographic, clinical, and laboratory data were obtained from patient records. CMV antibody was analyzed by chemiluminescent microparticle immunoassay and viremia by quantitative PCR.

Results: All patients were CMV-seropositive. At baseline 38 (22.6%) had detectable CMV viremia and 14 (8.3%) had a CMV viral load ≥ 200 copies/ml. In 135 patients available for follow-up, CMV ≥ 200 copies/ml was an independent risk factor for death with a hazard ratio of 5.0 (95% confidence interval 2.1-11.9) after adjusting for confounders. Symptoms compatible with CMV disease were common with viremia ≥ 200 copies/ml and CD4+ T cell counts <100 cells/mm(3), but confirmatory diagnostic procedures were unavailable.

Conclusions: DBS are suitable for the detection of CMV antibody and viremia in HIV patients in resource-poor areas. CMV viremia was frequent and associated with an increased risk of death. Improved diagnosis and treatment of CMV may improve the prognosis for HIV-infected patients in developing countries and should be addressed in future studies.
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http://dx.doi.org/10.1016/j.ijid.2012.08.003DOI Listing
December 2012

Comparison of PCR with culture applied on nasopharyngeal and throat swab specimens for the detection of Bordetella pertussis.

Scand J Infect Dis 2011 Mar 25;43(3):221-4. Epub 2010 Nov 25.

Department of Microbiology, Oslo University Hospital, Ullevål, Norway.

An in-house nested polymerase chain reaction (PCR) was prospectively compared with culture for Bordetella pertussis detection in 435 nasopharyngeal and/or throat swabs from 304 patients. One hundred specimens - 21% of nasopharyngeal swabs and 25% of throat swabs - were PCR- and/or culture-positive. Seventy percent of positive nasopharyngeal samples and 44% of positive throat samples were culture-positive.
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http://dx.doi.org/10.3109/00365548.2010.538855DOI Listing
March 2011

HIV type-1 drug resistance testing on dried blood spots is feasible and reliable in patients who fail antiretroviral therapy in rural Tanzania.

Antivir Ther 2010 ;15(7):1003-9

Department of Infectious Diseases, Oslo University Hospital, Ullevål, Oslo, Norway.

Background: HIV type-1 (HIV-1) drug resistance testing is rarely available in resource-limited settings because of high costs and stringent requirements for storage and transport of plasma. Dried blood spots (DBS) can be a convenient alternative to plasma, but the use of DBS needs validation under field conditions. We assessed the performance of DBS in genotypic resistance testing of patients who failed first-line antiretroviral therapy (ART) in rural Tanzania.

Methods: A total of 36 ART-experienced patients with viral loads >1,000 copies/ml (median 15,180 copies/ml [range 1,350-3,683,000]) and with various HIV-1 subtypes were selected for resistance testing. DBS were stored with desiccant at ambient temperature for a median of 29 days (range 8-89). Samples were amplified using an in-house reverse transcriptase-nested PCR method and sequenced using the ViroSeq™ assay (Abbott Molecular, Des Plaines, IL, USA). DBS-derived genotypes were compared with genotypes from plasma.

Results: Overall, 34 of 36 (94%) DBS specimens were successfully genotyped. In the protease region, of 142 polymorphisms found in plasma, 132 (93%) were also detected in DBS. In the reverse transcriptase region, of 57 clinically relevant mutations present in plasma, 51 (89%) were also detected in DBS. A total of 30 of 34 (88%) patients had identical resistance profiles to antiretroviral drugs in plasma and DBS.

Conclusions: Genotyping was successful in the vast majority of DBS specimens stored at ambient temperature for up to 3 months, and there was high concordance between mutations found in DBS and plasma. Our study suggests that DBS can be a feasible and reliable tool to monitor HIV-1 drug resistance in patients on ART in resource-limited settings.
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http://dx.doi.org/10.3851/IMP1660DOI Listing
February 2011

Drug resistance is widespread among children who receive long-term antiretroviral treatment at a rural Tanzanian hospital.

J Antimicrob Chemother 2010 Sep 24;65(9):1996-2000. Epub 2010 Jun 24.

Department of Infectious Diseases, Oslo University Hospital, Ulleval, Oslo, Norway.

Objectives: To assess long-term virological efficacy and the emergence of drug resistance in children who receive antiretroviral treatment (ART) in rural Tanzania.

Patients And Methods: Haydom Lutheran Hospital has provided ART to HIV-infected individuals since 2003. From February through May 2009, a cross-sectional virological efficacy survey was conducted among children (<15 years) who had completed >or=6 months of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Genotypic resistance was determined in those with a viral load of >200 copies/mL.

Results: Virological response was measured in 19 of 23 eligible children; 8 of 19 were girls and median age at ART initiation was 5 years (range 2-14 years). Median duration of ART at the time of the survey was 40 months (range 11-61 months). Only 8 children were virologically suppressed (
Conclusions: Among children on long-term ART in rural Tanzania, >50% harboured drug resistance. Results for children were markedly poorer than for adults attending the same programme, underscoring the need for improved treatment strategies for children in resource-limited settings.
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http://dx.doi.org/10.1093/jac/dkq234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920178PMC
September 2010

A multidrug-resistant, methicillin-susceptible strain of Staphylococcus aureus from a neonatal intensive care unit in Oslo, Norway.

Scand J Infect Dis 2010 ;42(2):148-51

Department of Microbiology, Oslo University Hospital, Ullevål, Oslo, Norway.

Over a 6-month period in 2008, approximately 15% of all Staphylococcus aureus isolates from our neonatal intensive care unit were resistant to penicillin, gentamicin, erythromycin and clindamycin. Extended antibiotic susceptibility testing and molecular profiling revealed an outbreak of an S. aureus strain with a rare susceptibility pattern for a Scandinavian setting.
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http://dx.doi.org/10.3109/00365540903334401DOI Listing
March 2010

Virological efficacy and emergence of drug resistance in adults on antiretroviral treatment in rural Tanzania.

BMC Infect Dis 2009 Jul 7;9:108. Epub 2009 Jul 7.

Ulleval Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.

Background: Virological response to antiretroviral treatment (ART) in rural Africa is poorly described. We examined virological efficacy and emergence of drug resistance in adults receiving first-line ART for up to 4 years in rural Tanzania.

Methods: Haydom Lutheran Hospital has provided ART to HIV-infected patients since October 2003. A combination of stavudine or zidovudine with lamivudine and either nevirapine or efavirenz is the standard first-line regimen. Nested in a longitudinal cohort study of patients consecutively starting ART, we carried out a cross-sectional virological efficacy survey between November 2007 and June 2008. HIV viral load was measured in all adults who had completed at least 6 months first-line ART, and genotypic resistance was determined in patients with viral load >1000 copies/mL.

Results: Virological response was measured in 212 patients, of whom 158 (74.5%) were women, and median age was 35 years (interquartile range [IQR] 29-43). Median follow-up time was 22.3 months (IQR 14.0-29.9). Virological suppression, defined as <400 copies/mL, was observed in 187 patients (88.2%). Overall, prevalence of > or =1 clinically significant resistance mutation was 3.9, 8.4, 16.7 and 12.5% in patients receiving ART for 1, 2, 3 and 4 years, respectively. Among those successfully genotyped, the most frequent mutations were M184I/V (64%), conferring resistance to lamivudine, and K103N (27%), Y181C (27%) and G190A (27%), conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), whereas 23% had thymidine analogue mutations (TAMs), associated with cross-resistance to all nucleoside reverse transcriptase inhibitors (NRTIs). Dual-class resistance, i.e. resistance to both NRTIs and NNRTIs, was found in 64%.

Conclusion: Virological suppression rates were good up to 4 years after initiating ART in a rural Tanzanian hospital. However, drug resistance increased with time, and dual-class resistance was common, raising concerns about exhaustion of future antiretroviral drug options. This study might provide a useful forecast of drug resistance and demand for second-line antiretroviral drugs in rural Africa in the coming years.
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http://dx.doi.org/10.1186/1471-2334-9-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713244PMC
July 2009

Overestimation of human immunodeficiency virus type 1 load caused by the presence of cells in plasma from plasma preparation tubes.

J Clin Microbiol 2009 Jul 6;47(7):2170-4. Epub 2009 May 6.

Department of Microbiology, Oslo University Hospital, Oslo, Norway.

The human immunodeficiency virus type 1 (HIV-1) load is an important marker of disease progression and treatment efficacy in patients with HIV-1 infection. In recent years, an increase in the number of samples with detectable HIV-1 RNA has been reported among patients with previously suppressed viral loads, affecting clinical patient care and leading to repeat measurements of viral load and drug resistance. This rise seems to have coincided with the increased use of plasma preparation tubes (PPTs) for sample collection, and we have aimed to explain why PPTs might yield elevated HIV-1 RNA levels. The impacts of different sample-processing procedures on HIV-1 RNA levels were compared retrospectively. Prospectively, the presence of different cells and cell-associated HIV-1 nucleic acids in paired plasma samples from PPTs centrifuged before (PPT1) and after (PPT2) transportation to the laboratory was compared. A retrospective analysis of 4,049 patient samples with <1,000 HIV-1 RNA copies/ml showed elevated HIV-1 RNA levels in plasma from PPT1 compared with the levels from PPT2 and standard EDTA-containing tubes. Prospective data revealed cell-associated HIV-1 nucleic acids and abundant blood cells in plasma from PPT1 but not from the corresponding PPT2. The levels of HIV-1 RNA correlated with the lymphocyte counts in plasma in PPT1. Cells could be removed by the recentrifugation of PPT1 before analysis. In conclusion, the transportation of PPTs after centrifugation may render cells in the plasma fraction containing cell-associated HIV-1 nucleic acids that contribute significantly to the HIV-1 RNA copy numbers in patients with low viral loads.
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http://dx.doi.org/10.1128/JCM.00519-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708492PMC
July 2009

Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment.

J Infect Dis 2008 Nov;198(10):1474-81

Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway.

Objective: Mitochondrial DNA (mtDNA) loss in peripheral blood mononuclear cells (PBMCs) has been found in both nucleoside reverse-transcriptase inhibitor (NRTI)-exposed and antiretroviral therapy (ART)-naive patients with human immunodeficiency virus (HIV) infection. Persistent immune activation might play a role in this phenomenon in HIV-infected, ART-naive patients. PBMC subsets with differential growth kinetics were therefore purified to study this similarity.

Methods: CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes were purified from PBMCs. mtDNA levels were quantified using real-time polymerase chain reaction and compared among the 2 groups of HIV-infected patients and a group of HIV-negative control subjects. mtDNA levels in a separate group of ART-naive patients stratified by the rate of disease progression were also evaluated with respect to their relationship to immune-activation markers (i.e., CD38 and programmed cell death-1 [PD-1]) on CD8(+) T cells and the rate of CD4(+) T cell loss.

Results: mtDNA levels in CD8(+) T cells and B cells from 15 ART-naive patients were approximately 50% less than those observed for 14 control subjects (P < or = .01). mtDNA levels in all lymphocyte subsets correlated negatively with CD38(+)PD-1(+) expression (r= -0.66 P < -0.9; P < or = .03), and mtDNA levels in B cells correlated with the rate of CD4(+) T cell loss (r =0.66; P< .3). In 17 HIV-infected, NRTI-exposed patients, mtDNA loss was observed in both T cell subsets (P < or = .02) and was most pronounced in patients who received didanosine (P < or = .002).

Conclusions: In HIV-infected, ART-naive patients, mtDNA loss was found in CD8(+) T cells and B cells. These losses correlated with immune activation and, in B cells, with the rate of CD4(+) T cell loss. In patients receiving ART, only T lymphocytes had reduced mtDNA levels. This finding was probably associated with NRTI use, because it was most pronounced in patients with a history of didanosine exposure.
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http://dx.doi.org/10.1086/592713DOI Listing
November 2008

CMV quantitative PCR in the diagnosis of CMV disease in patients with HIV-infection - a retrospective autopsy based study.

BMC Infect Dis 2007 Nov 6;7:127. Epub 2007 Nov 6.

Department of Infectious Diseases, Ullevaal University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: Patients with advanced HIV infection at the time of diagnosis and patients not responding to antiretroviral therapy are at risk of cytomegalovirus (CMV) disease. Earlier studies of patients with HIV infection have demonstrated that the diagnosis is often first made post-mortem. In recent years new molecular biological tests have become available for diagnosis of CMV disease. Although clinical evaluation of tests for diagnosis of CMV disease in HIV-infected individuals is suboptimal without autopsy, no results from such studies have been published. The aim of this study was to explore the diagnostic utility of CMV quantitative polymerase chain reaction (PCR) in plasma from HIV and CMV seropositive patients who died during the period 1991-2002 and in whom autopsy was performed.

Methods: Autopsy was performed in all cases, as part of routine evaluation of HIV-infected cases followed at Ullevaal University Hospital. Of 125 patients included, 53 had CMV disease, 37 of whom were first diagnosed at autopsy. CMV disease was diagnosed either by ophthalmoscopic findings typical of CMV retinitis, biopsy or autopsy. One or two plasma samples taken prior to the first diagnosis of CMV disease (alive or at autopsy) or death without CMV disease were analysed by CMV quantitative PCR. Sensitivity, specificity, positive and negative predictive values were calculated for different CMV viral load cut-offs and according to detection of viraemia in one versus two samples.

Results: Twenty-seven of 53 patients with CMV disease (51%) and 10 of 72 patients without CMV disease (14%) had detectable viraemia in at least one sample. Sensitivity and negative predictive value (NPV) of the test, maximised with a cut-off at the test's limit of detection of CMV viraemia (400 copies/mL), were 47% and 70%, respectively. With cut-off at 10 000 copies/mL, specificity and positive predictive value (PPV) were 100%. With a requirement for CMV viraemia in two samples, specificity and PPV were 100% in patients with CMV viraemia above the limit of detection.

Conclusion: Our results indicate that quantitative CMV PCR is best used to rule in, rather than to rule out CMV disease in HIV-infected individuals at high risk.
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http://dx.doi.org/10.1186/1471-2334-7-127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194717PMC
November 2007

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.

Hepatology 2008 Jan;47(1):35-42

Infectious Disease Department, Ullevål University Hospital, Oslo, Norway.

Unlabelled: A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment-naïve HCV RNA-positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon alpha-2b (1.5 microg/kg) subcutaneously weekly and ribavirin (800-1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one-sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention-to-treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7-17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, -0.1 to +13.9).

Conclusion: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks.
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http://dx.doi.org/10.1002/hep.21975DOI Listing
January 2008

Insulin resistance is affected by increased levels of plasma lactate but not mitochondrial alterations in skeletal muscle in NRTI-exposed HIV-infected patients.

HIV Clin Trials 2007 Sep-Oct;8(5):345-53

Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway.

Purpose: To explore the relations between insulin resistance, plasma lactate, and mitochondrial (mt) DNA alterations in skeletal muscle in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors (HIV+NRTI+).

Method: Insulin resistance was estimated using the homeostatic model assessment (HOMA-IR). Mitochondrial dysfunction was determined by plasma lactate at rest and after subanaerobic exercise, mitochondrial/nuclear DNA (mt/nDNA) ratio, and mtDNA deletions in skeletal muscle.

Results: HIV+NRTI+ patients (n = 27) had higher levels of HOMA-IR, higher lactate at rest as well as after exercise, and more frequent mtDNA deletions and decreased mt/nDNA ratios compared with controls (n = 15). Only in HIV+NRTI+ patients, HOMA-IR correlated with resting lactate (r = 0.5, p = .02) and probably also lactate 3, 5, and 8 minutes after exercise (r = 0.4; p = .075, p = .048, and p = .056, respectively). In contrast, neither HOMA-IR nor the lactate levels correlated with mt/nDNA ratio and mtDNA deletions in skeletal muscle in HIV+NRTI+ patients (r < 0.1, p > .6), whereas resting lactate correlated with mt/nDNA ratio in HIV seronegative controls (r = -0.7, p = .02).

Conclusion: In HIV+NRTI+ patients, both resting and postexercise levels of lactate were related to insulin resistance rather than mtDNA alterations in skeletal muscle.
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http://dx.doi.org/10.1310/hct0805-345DOI Listing
December 2007

Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study.

BMC Infect Dis 2007 May 22;7:43. Epub 2007 May 22.

Department of Medicine, Haukeland University Hospital, Bergen, Norway.

Background: Bloodstream infection is a common cause of hospitalization, morbidity and death in children. The impact of antimicrobial resistance and HIV infection on outcome is not firmly established.

Methods: We assessed the incidence of bloodstream infection and risk factors for fatal outcome in a prospective cohort study of 1828 consecutive admissions of children aged zero to seven years with signs of systemic infection. Blood was obtained for culture, malaria microscopy, HIV antibody test and, when necessary, HIV PCR. We recorded data on clinical features, underlying diseases, antimicrobial drug use and patients' outcome.

Results: The incidence of laboratory-confirmed bloodstream infection was 13.9% (255/1828) of admissions, despite two thirds of the study population having received antimicrobial therapy prior to blood culture. The most frequent isolates were klebsiella, salmonellae, Escherichia coli, enterococci and Staphylococcus aureus. Furthermore, 21.6% had malaria and 16.8% HIV infection. One third (34.9%) of the children with laboratory-confirmed bloodstream infection died. The mortality rate from Gram-negative bloodstream infection (43.5%) was more than double that of malaria (20.2%) and Gram-positive bloodstream infection (16.7%). Significant risk factors for death by logistic regression modeling were inappropriate treatment due to antimicrobial resistance, HIV infection, other underlying infectious diseases, malnutrition and bloodstream infection caused by Enterobacteriaceae, other Gram-negatives and candida.

Conclusion: Bloodstream infection was less common than malaria, but caused more deaths. The frequent use of antimicrobials prior to blood culture may have hampered the detection of organisms susceptible to commonly used antimicrobials, including pneumococci, and thus the study probably underestimates the incidence of bloodstream infection. The finding that antimicrobial resistance, HIV-infection and malnutrition predict fatal outcome calls for renewed efforts to curb the further emergence of resistance, improve HIV care and nutrition for children.
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http://dx.doi.org/10.1186/1471-2334-7-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1891109PMC
May 2007

Mitochondrial (mt)DNA changes in tissue may not be reflected by depletion of mtDNA in peripheral blood mononuclear cells in HIV-infected patients.

Antivir Ther 2006 ;11(5):601-8

Department of Infectious Diseases, Ullevaal University Hospital, Oslo, Norway.

Objectives: Most data on mitochondrial toxicity have been derived from peripheral blood mononuclear cells (PBMCs). However, whether mitochondrial DNA (mtDNA) content in PBMCs reflects the mitochondrial state in tissues remains elusive. We report herein on mitochondrial toxicity in skeletal muscle in HIV-infected patients naive to antiretroviral treatment (ART [HIV+ART-naive]; n = 10) patients exposed to nucleoside reverse transcriptase inhibitors (NRTIs [HIV+NRTI+]; n = 24) and healthy controls (n = 11), and compare these tissue data with mtDNA in PBMCs.

Methods: Muscle biopsies were examined for (i) mtDNA and nuclear DNA (nDNA) content using TaqMan real-time PCR system, (ii) mtDNA deletions using long expand PCR with subsequent gel electrophoresis, and (iii) mitochondrial myopathy expressed as cytochrome c oxidase (COX)-deficient muscle fibres.

Results: The mt/n DNA ratio in muscle from HIV+NRTI+ patients was reduced compared with HIV-negative controls (P = 0.028). Moreover, mtDNA deletions were more frequent in HIV+NRTI+ patients than in both HIV-negative controls (P = 0.009) and HIV+ART-naive patients (P = 0.005). HIV+NRTI+ also tended to have more COX-deficient fibres than HIV-negative controls (P = 0.076). COX-deficient fibres were positively correlated with mtDNA deletions in HIV+NRTI+ patients (r = 0.83, P < 0.001). Patients with current use of didanosine (ddl) had more frequent mtDNA deletions and COX-deficient fibres than HIV+NRTI+ not on current treatment with ddl. It should be noted that mitochondrial alterations were not correlated with mtDNA/cell in PBMCs in any group.

Conclusions: In skeletal muscle, HIV+NRTI+ had a reduced mt/n DNA ratio, more frequent mtDNA deletions and possibly more COX-deficient muscle fibres than HIV-negative controls. However, the mtDNA/cell in peripheral blood was decreased in both HIV+NRTI+ and HIV+ART-naive patients. Thus, mtDNA in peripheral blood may not be a relevant marker of mitochondrial toxicity in organ-specific tissue.
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August 2007

HIV genetic diversity in Cameroon: possible public health importance.

AIDS Res Hum Retroviruses 2006 Aug;22(8):812-6

Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, Georgia 30333, USA.

To monitor the evolving molecular epidemiology and genetic diversity of HIV in a country where many distinct strains cocirculate, we performed genetic analyses on sequences from 75 HIV-1-infected Cameroonians: 74 were group M and 1 was group O. Of the group M sequences, 74 were classified into the following env gp41 subtypes or recombinant forms: CRF02 (n = 54), CRF09 (n = 2), CRF13 (n = 2), A (n = 5), CRF11 (n = 4), CRF06 (n = 1), G (n = 2), F2 (n = 2), and E (n = 1, CRF01), and 1 was a JG recombinant. Comparison of phylogenies for 70 matched gp41 and protease sequences showed inconsistent classifications for 18 (26%) strains. Our data show that recombination is rampant in Cameroon with recombinant viruses continuing to recombine, adding to the complexity of circulating HIV strains. This expanding genetic diversity raises public health concerns for the ability of diagnostic assays to detect these unique HIV mosaic variants and for the development of broadly effective HIV vaccines.
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http://dx.doi.org/10.1089/aid.2006.22.812DOI Listing
August 2006

Prognostic value of changes in CD4 count and HIV RNA during the first six months on highly active antiretroviral therapy in chronic human immunodeficiency virus infection.

Scand J Infect Dis 2003 ;35(6-7):383-8

Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway.

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-naive 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 (deltaCD4) from therapy initiation: groups A (n = 37, deltaCD4 < 0.052 x 10(9)/l) and B (n = 111, deltaCD4 > or = 0.052 x 10(9)/l). Patients were also stratified according to achievement of HIV RNA < 400 copies/ml (n = 122) or > 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 > or = copies/ml versus reaching viral suppression < 400 copies/ml was associated with an increased risk of HIV-related disease only in patients with deltaCD4 < 0.052 x 10(9)/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.
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http://dx.doi.org/10.1080/00365540310009716DOI Listing
September 2003

[Transmission of methicillin resistant Staphylococcus aureus to primary health care workers in a home environment].

Tidsskr Nor Laegeforen 2003 Feb;123(3):319-21

Medisinsk avdeling Sentralsjukehuset i Rogaland Postboks 8100, 4068 Stavanger.

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February 2003

A search for optimal criteria in initiating antiretroviral therapy in chronic human immunodeficiency virus infection focusing on CD4 count and HIV RNA.

Scand J Infect Dis 2002 ;34(12):910-7

Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway.

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.
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http://dx.doi.org/10.1080/0036554021000026957DOI Listing
March 2003