Publications by authors named "Johan N Bruun"

44 Publications

Achievements and Challenges in the Prevention of Mother-to-Child Transmission of HIV-A Retrospective Cohort Study from a Rural Hospital in Northern Tanzania.

Int J Environ Res Public Health 2021 03 9;18(5). Epub 2021 Mar 9.

Department of Infectious Diseases, Ullevål Hospital, Oslo University Hospital, P.O. Box 4956, Nydalen, 0424 Oslo, Norway.

Despite the goal of eliminating new human immunodeficiency virus (HIV) infections in children, mother-to-child transmission is still common in resource-poor countries. The aims of this study were to assess the occurrence of mother-to-child transmission of HIV (MTCT) by age 18 months, risk factors for transmission, and the implementation of the national prevention of MTCT (PMTCT) program in a rural hospital in Tanzania. Data were collated from various medical registers and records. We included 172 children and 167 HIV-infected mothers. Among 88 children (51%) with adequate information, 9 (10.2%) were infected. Increased risk of MTCT was associated with late testing of the child (>2 months) [OR = 9.5 (95% CI: 1.8-49.4)], absence of antiretroviral therapy during pregnancy [OR = 9.7 (95% CI: 2.1-46.1)], and maternal CD4 cell count <200 cells/mm [OR = 15.3 (95% CI: 2.1-111)]. We were unable to determine the occurrence of MTCT transmission in 84 children (49%). The results from this study highlight that there is an urgent need for enhanced efforts to improve follow-up of HIV-exposed children, to improve documentation in registries and records, and to facilitate ease of linkage between these.
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http://dx.doi.org/10.3390/ijerph18052751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967482PMC
March 2021

Infectious diseases among patients at the Health Centre for Undocumented Migrants in Oslo.

Tidsskr Nor Laegeforen 2020 03 16;140(4). Epub 2020 Mar 16.

Background: Undocumented migrants probably fall outside the scope of public infectious disease control schemes. The article aims to describe the extent of undetected highly hazardous communicable diseases among patients at the Health Centre for Undocumented Migrants in Oslo.

Material And Method: We reviewed the records of all patients who attended the Health Centre for the first time in 2016 or 2017, with a view to age, sex, period of stay in Norway, country category and infection test results from the period 1 January 2016-31 December 2017.

Results: There were four new cases of hepatitis B among 139 patients tested, and four cases of chlamydia infection among 38 patients tested. There were no new cases of active pulmonary tuberculosis, syphilis, HIV infection or hepatitis C.

Interpretation: There were fewer cases of highly hazardous communicable diseases than what might be expected based on the countries from which the patients originated.
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http://dx.doi.org/10.4045/tidsskr.19.0074DOI Listing
March 2020

Antiretroviral treatment failure predicts mortality in rural Tanzania.

Int J STD AIDS 2015 Aug 13;26(9):633-9. Epub 2014 Aug 13.

Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway Vestre Viken HF, Drammen Hospital, Drammen, Norway

Virological monitoring of HIV-infected patients on antiretroviral treatment (ART) is rarely available in resource-limited settings and many patients experience unrecognized virological failure. We studied the long-term consequences of virological failure in rural Tanzania. Previously, virological efficacy was measured in a cohort treated with ART. In the present study, patients with virological failure (VF; HIV-RNA >400 copies/ml) were followed up and compared to those with virological response (VR; HIV-RNA <400 copies/ml) with regard to mortality, CD4 change and subsequent virological outcome. Fifty-six patients with VF had a median CD4 count of 358 cells/µl (interquartile range [IQR] 223-635) and a median HIV-RNA of 13,573 copies/ml (IQR 2326-129,736). Median CD4 count for those with VR was 499 cells/µl (IQR 290-636). During a median follow-up time of 39 months (IQR 18-42), 8 of 56 patients (14.3%) with VF died, compared to 1 of 63 patients (1.6%) with VR (p = 0.009). All registered deaths were HIV-related. Of 55 patients with subsequent HIV-RNA measurements, only 12 of 30 (40%) patients with VF achieved virological suppression, compared to 20 of 25 (80%) patients with VR (p = 0.003). Virological failure predicted death and subsequent virological failure in patients on ART in a resource-limited setting.
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http://dx.doi.org/10.1177/0956462414548460DOI Listing
August 2015

[Antibiotic politics, infection control and ethics].

Authors:
Johan N Bruun

Tidsskr Nor Laegeforen 2013 Sep;133(17):1793

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http://dx.doi.org/10.4045/tidsskr.13.0961DOI Listing
September 2013

Viruses out travelling.

Authors:
Johan N Bruun

Tidsskr Nor Laegeforen 2012 Nov;132(21):2404

Department of Internal Medicine, University Hospital of North Norway, Norway.

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http://dx.doi.org/10.4045/tidsskr.12.1067DOI Listing
November 2012

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

Tourism, climate change and diagnostics.

Authors:
Johan N Bruun

Tidsskr Nor Laegeforen 2012 Mar;132(6):670-1

Department of Infectious Diseases, University Hospital of North Norway, andUniversity of Tromsø, Norway.

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http://dx.doi.org/10.4045/tidsskr.11.1467DOI Listing
March 2012

Antiretroviral treatment reverses HIV-associated anemia in rural Tanzania.

BMC Infect Dis 2011 Jul 11;11:190. Epub 2011 Jul 11.

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

Background: HIV-associated anemia is common and associated with poor prognosis. However, its response to antiretroviral treatment (ART) in rural Africa is poorly understood.

Methods: HIV-infected adults (≥15 years) who enrolled in HIV care at Haydom Lutheran Hospital in northern Tanzania were included in the study. The effect of ART (zidovudine/stavudine + lamivudine + efavirenz/nevirapine) on HIV-associated anemia was studied in a subset of patients who were anemic at the time they started ART and had a follow-up hemoglobin measurement 12 months later. Pregnant women were excluded from the study, as were women who had given birth within the past 6 weeks. Anemia was defined as hemoglobin <12 g/dL in women and <13 g/dL in men. We applied paired sample T-tests to compare hemoglobin levels before and one year after ART initiation, and logistic regression models to identify predictors of persistent anemia.

Results: At enrollment, mean hemoglobin was 10.3 g/dL, and 649 of 838 patients (77.4%) were anemic. Of the anemic patients, 254 (39.1%) had microcytosis and hypochromia. Among 102 patients who were anemic at ART initiation and had a follow-up hemoglobin measurement after 12 months, the mean hemoglobin increased by 2.5 g/dL (P < 0.001); however, 39 patients (38.2%) were still anemic after 12 months of ART. Independent predictors of persistent anemia were mean cell volume in the lower quartile (<76.0 fL; Odds Ratio [OR] 4.34; 95% confidence interval [CI] 1.22-15.5) and a zidovudine-containing initial regimen (OR 2.91; 95% CI 1.03-8.19).

Conclusions: Most patients had anemia at enrollment, of whom nearly 40% had microcytosis and hypochromia suggestive of iron deficiency. The mean hemoglobin increased significantly in patients who received ART, but one third were still anemic 12 months after ART initiation indicating that additional interventions to treat HIV-associated anemia in rural Africa might be warranted, particularly in patients with microcytosis and those treated with zidovudine.
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http://dx.doi.org/10.1186/1471-2334-11-190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145581PMC
July 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

[Some diseases will come back].

Authors:
Johan N Bruun

Tidsskr Nor Laegeforen 2010 Oct;130(20):2028-9

Universitetssykehuset Nord Norge, 9038 Tromsø, Norway.

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http://dx.doi.org/10.4045/tidsskr.10.0916DOI Listing
October 2010

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

[Immune reconstitution inflammatory syndrome and treatment of HIV infection].

Tidsskr Nor Laegeforen 2009 Dec;129(23):2484-7

Medisinsk avdeling, Oslo universitetssykehus, Ullevål og Leger Uten Grenser, Postboks 8813 Youngstorget, 0028 Oslo, Norway.

Background: HAART (highly active antiretroviral therapy) may trigger a condition known as IRIS (immune reconstitution inflammatory syndrome); i.e. a paradoxical reaction to latent infections associated with reconstitution of the immune system. The article provides an overview of the syndrome and discusses diagnosis, risk factors and management.

Material And Methods: The basis for the article was literature identified through non-systematic searches in PubMed and clinical experience.

Results: IRIS typically occurs some weeks to months after initiation of HAART, usually in association with mycobacterial infections, cytomegalovirus, Cryptococcus neoformans and Pneumocystis jirovecii. In principle, any pathogen may cause a similar inflammatory response. Risk factors for IRIS include severe immunodeficiency, high antigen burden and rapid immune response to HAART. The prognosis is good. However, treatment of infections must not delay the initiation of HAART, as such a delay may increase morbidity and mortality. HAART should be continued unless symptoms are life-threatening or likely to cause permanent sequelae. Corticosteroids may be helpful in cases with lesions in the central nervous system, obstructive lymph nodes or increasing respiratory symptoms.

Interpretation: Treatment of HIV infection has improved substantially, which implies an increased number of patients developing IRIS. A quick diagnosis and correct and timely treatment of opportunistic infections is important for the prognosis.
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http://dx.doi.org/10.4045/tidsskr.09.0190DOI Listing
December 2009

Dried blood spots perform well in viral load monitoring of patients who receive antiretroviral treatment in rural Tanzania.

Clin Infect Dis 2009 Sep;49(6):976-81

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

Background: Monitoring of antiretroviral treatment (ART) with human immunodeficiency virus (HIV) viral loads, as recommended in industrialized countries, is rarely available in resource-limited settings because of the high costs and stringent requirements for storage and transport of plasma. Dried blood spots (DBS) can be an alternative to plasma, but the use of DBS has not been assessed under field conditions in rural Africa. The present study investigates the performance of DBS in HIV viral load monitoring of patients who received ART in rural Tanzania.

Patients And Methods: From November 2007 through June 2008, parallel plasma and DBS specimens were obtained from patients who received ART at Haydom Lutheran Hospital in rural Tanzania. DBS specimens were stored at tropical room temperature for 3 weeks before testing with the NucliSENS EasyQ HIV-1 v1.2 assay. Results obtained with DBS were compared with results obtained with use of a gold-standard plasma assay.

Results: Ninety-eight plasma-DBS pairs were compared, and plasma viral loads ranged from <40 to >1,000,000 copies/mL. The correlation between plasma and DBS viral load was strong (R(2) = 0.75). The mean difference (+/- standard deviation) was 0.04 +/ 0.57 log(10) copies/mL, and only 8 samples showed >1 log(10) copies/mL difference. HIV type 1 RNA was detected in 7%, 60%, and 100% of DBS specimens with corresponding plasma viral loads of 40-999, 1000-2999, and 3000 copies/mL, respectively.

Conclusions: DBS, in combination with the NucliSENS EasyQ HIV-1 v1.2 asay, performed well in monitoring HIV viral loads in patients who received ART in rural Tanzania, although the sensitivity was reduced when viral burden was low. The use of DBS can simplify virological monitoring in resource-limited settings.
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http://dx.doi.org/10.1086/605502DOI Listing
September 2009

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

Immunohaematological reference values in human immunodeficiency virus-negative adolescent and adults in rural northern Tanzania.

BMC Infect Dis 2009 Jan 13;9. Epub 2009 Jan 13.

Haydom Lutheran Hospital, Mbulu District, Manyara Region, Tanzania.

Background: The amount of CD4 T cells is used for monitoring HIV progression and improvement, and to make decisions to start antiretroviral therapy and prophylactic drugs for opportunistic infections. The aim of this study was to determine normal reference values for CD4 T cells, lymphocytes, leucocytes and haemoglobin level in healthy, HIV negative adolescents and adults in rural northern Tanzania.

Methods: A cross sectional study was conducted from September 2006 to March 2007 in rural northern Tanzania. Participants were recruited from voluntary HIV counselling and testing clinics. Patients were counselled for HIV test and those who consented were tested for HIV. Clinical screening was done, and blood samples were collected for CD4 T cell counts and complete blood cell counts.

Results: We enrolled 102 participants, forty two (41.2%) males and 60 (58.8%) females. The mean age was 32.6 +/- 95% CI 30.2-35.0. The mean absolute CD4 T cell count was 745.8 +/- 95% CI 695.5-796.3, absolute CD8 T cells 504.6 +/- 95% CI 461.7-547.5, absolute leukocyte count 5.1 +/- 95% CI 4.8-5.4, absolute lymphocyte count 1.8 +/- 95% CI 1.7-1.9, and haemoglobin level 13.2 +/- 95% CI 12.7-13.7. Females had significantly higher mean absolute CD4 T cell count (p = 0.008), mean absolute CD8 T cell count (p = 0.009) and significantly lower mean haemoglobin level than males (p = 0.003)

Conclusion: Immunohaematological values found in this study were different from standard values for western countries. Females had significantly higher mean CD4 T cell counts and lower mean haemoglobin levels than males. This raises the issue of the appropriateness of the present reference values and guidelines for monitoring HIV/AIDS patients in Tanzania.
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http://dx.doi.org/10.1186/1471-2334-9-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630915PMC
January 2009

Pulmonary tuberculosis among people living with HIV/AIDS attending care and treatment in rural northern Tanzania.

BMC Public Health 2008 Sep 30;8:341. Epub 2008 Sep 30.

Haydom Lutheran Hospital, Mbulu District, Manyara Region, Tanzania.

Background: Tuberculosis is the commonest opportunistic infection and the number one cause of death in HIV/AIDS patients in developing countries. To address the extent of the tuberculosis HIV coinfection in rural Tanzania we conducted a cross sectional study including HIV/AIDS patients attending care and treatment clinic from September 2006 to March 2007.

Methods: Sputum samples were collected for microscopy, culture and drug susceptibility testing. Chest X-ray was done for those patients who consented. Blood samples were collected for CD4+ T cells count.

Results: The prevalence of tuberculosis was 20/233 (8.5%). Twenty (8.5%) sputum samples were culture positive. Eight of the culture positive samples (40%) were smear positive. Fifteen (75%) of these patients neither had clinical symptoms nor chest X-ray findings suggestive of tuberculosis. Nineteen isolates (95%) were susceptible to rifampicin, isoniazid, streptomycin and ethambutol (the first line tuberculosis drugs). One isolate (5%) from HIV/tuberculosis coinfected patients was resistant to isoniazid. No cases of multi- drug resistant tuberculosis were identified.

Conclusion: We found high prevalence of tuberculosis disease in this setting. Chest radiograph suggestive of tuberculosis and clinical symptoms of fever and cough were uncommon findings in HIV/tuberculosis coinfected patients. Tuberculosis can occur at any stage of CD4+T cells depletion.
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http://dx.doi.org/10.1186/1471-2458-8-341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566981PMC
September 2008

Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania.

BMC Infect Dis 2008 Apr 22;8:52. Epub 2008 Apr 22.

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

Background: Studies of antiretroviral therapy (ART) programs in Africa have shown high initial mortality. Factors contributing to this high mortality are poorly described. The aim of the present study was to assess mortality and to identify predictors of mortality in HIV-infected patients starting ART in a rural hospital in Tanzania.

Methods: This was a cohort study of 320 treatment-naïve adults who started ART between October 2003 and November 2006. Reliable CD4 cell counts were not available, thus ART initiation was based on clinical criteria in accordance with WHO and Tanzanian guidelines. Kaplan-Meier models were used to estimate mortality and Cox proportional hazards models to identify predictors of mortality.

Results: Patients were followed for a median of 10.9 months (IQR 2.9-19.5). Overall, 95 patients died, among whom 59 died within 3 months of starting ART. Estimated mortality was 19.2, 29.0 and 40.7% at 3, 12 and 36 months, respectively. Independent predictors of mortality were severe anemia (hemoglobin <8 g/dL; adjusted hazard ratio [AHR] 9.20; 95% CI 2.05-41.3), moderate anemia (hemoglobin 8-9.9 g/dL; AHR 7.50; 95% CI 1.77-31.9), thrombocytopenia (platelet count <150 x 109/L; AHR 2.30; 95% CI 1.33-3.99) and severe malnutrition (body mass index <16 kg/m2; AHR 2.12; 95% CI 1.06-4.24). Estimated one year mortality was 55.2% in patients with severe anemia, compared to 3.7% in patients without anemia (P < 0.001).

Conclusion: Mortality was found to be high, with the majority of deaths occurring within 3 months of starting ART. Anemia, thrombocytopenia and severe malnutrition were strong independent predictors of mortality. A prognostic model based on hemoglobin level appears to be a useful tool for initial risk assessment in resource-limited settings.
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http://dx.doi.org/10.1186/1471-2334-8-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364629PMC
April 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

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

HIV related and non-HIV related mortality before and after the introduction of highly active antiretroviral therapy (HAART) in Norway compared to the general population.

Scand J Infect Dis 2007 ;39(1):51-7

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

The objective of the study was to compare the mortality in HIV infected individuals to the general population, and to explore the relative contribution of HIV to mortality before and after the introduction of highly active antiretroviral therapy (HAART). All HIV patients attending Ullevål University Hospital, Oslo, Norway before (cohort 1) and after (cohort 2) the introduction of HAART were included. Causes of deaths were classified as HIV related or not. Mortality in the Norwegian general population was standardized according to the distribution of age and gender in our cohorts. Ratios between mortality in our cohorts and the standardized mortality were calculated. The risk ratio (RR) for 5-y mortality compared to the general population was 22.6 (95% confidence interval (CI), 19.5-26.4) in cohort 1 (n = 782), and 3.96 (95% CI 2.25-6.97) in cohort 2 (n = 398). The non-HIV related mortality RR was 4.42 (95% CI 3.18-6.13) in cohort1 and 0.89 (95% CI 0.29-2.76) in cohort 2. Higher age and low CD4 cell count were associated with increased mortality. Thus, in the HAART era the mortality in HIV patients was reduced by 80%. However, the mortality in the HAART era was still 4 times higher than in the general population.
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http://dx.doi.org/10.1080/00365540600904779DOI Listing
April 2007

A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial.

Antivir Ther 2006 ;11(6):761-70

Copenhagen HIV Programme (CHIP), Hvidovre University Hospital, Copenhagen, Denmark.

Background: Lamivudine (3TC) therapy can cause the emergence of M1841/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M1841/V in patients receiving combination antiretroviral therapy (cART).

Methods: HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log10 average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and > or =1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M1841/V.

Results: The overall 48-week log10 HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC (n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC (n=66; P=0.51). No difference was seen in the magnitude of the CD4+ T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients (P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M18411V (P<0.0001).

Conclusion: This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M1841/V. Evolutionary distances from baseline were larger in viruses that did not contain M1841/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M1841/V in COLATE.
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March 2007

[HIV/AIDS--from lethal syndrome to chronic disease].

Tidsskr Nor Laegeforen 2006 Nov;126(23):3121-4

Infeksjonsmedisinsk avdeling Ullevål universitetssykehus 0407 Oslo.

Background: At its discovery in 1981, AIDS was a fatal syndrome that rapidly led to death. Combination treatment with at least three drugs has radically improved the prognosis.

Material And Methods: The study includes all HIV-patients controlled at the Department of Infectious Diseases, Ullevål University Hospital from 1982 to 2005. Development of immune deficiency, morbidity and causes of death were registered prospectively. Possible connections between death and HIV-infection and treatment were evaluated.

Results: 1632 patients were followed at our department. 32 % of these patients have died. The number of patients who died annually during the 5 years from 1986 to 1990 was 47 % and this was reduced to 11 % in 2001 - 05. Many patients still die because they either present too late for treatment or have received insufficient treatment. 22 patients have died during the last 10 years irrespective of starting treatment with at least 3 antiretroviral drugs: 7 died from cancers, 6 from treatment failure, one from unknown cause and 8 from other causes. The 6 patients who died from treatment failure had very low CD4 counts and serious opportunistic infections that could not be treated effectively at the time of diagnosis.

Interpretation: Patients who start and adhere to treatment with 3 HIV-medications have a good prognosis, but they may still have an increased risk of non-AIDS defining cancers and cardiovascular disease. HIV/AIDS has become a chronic disease with a good prognosis.
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November 2006

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

Important differences in components of the metabolic syndrome between HIV-patients with and without highly active antiretroviral therapy and healthy controls.

Scand J Infect Dis 2006 ;38(8):682-9

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

The aim of this study was to compare the prevalence of metabolic syndrome and insulin resistance in HIV-positive patients with and without HAART and healthy HIV-negative controls. In total 357 subjects were examined: 56 HIV-positive HAART-naïve, 207 HIV-positive on HAART treatment and 94 HIV-negative controls. We measured blood pressure, abdominal circumference, weight and height, and fasting serum levels of glucose, insulin and lipids in all the subjects. The presence of lipodystrophy was assessed in the HAART-treated patients. In non-overweight subjects the prevalence of the metabolic syndrome was 15% (25 of 162) in HAART-treated patients, 2% (1 of 44) in HAART-naïve (p=0.019) and 2% (1 of 45) in controls (p=0.020). The prevalence of insulin resistance in non-overweight subjects was also higher in HAART-treated than in controls, 39% vs 18% (p=0.012) but similar to HAART-naïve, 32% (p = 0.48 vs HAART, p = 0.22 vs controls). In non-overweight patients with lipodystrophy the metabolic syndrome was diagnosed in 21% and insulin resistance in 49%. In the entire HAART group 25% had the metabolic syndrome and/or insulin resistance without having lipodystrophy. We conclude that fasting glucose, HDL-cholesterol, triglycerides and blood pressure should be closely monitored in all HAART-treated patients, not only in overweighed or lipodystrophic individuals.
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http://dx.doi.org/10.1080/00365540500361302DOI Listing
October 2006

Serum concentrations of protease inhibitors as predictors of HIV-related clinical events in patients on antiretroviral therapy.

Scand J Infect Dis 2006 ;38(8):650-3

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

Serum concentrations of protease inhibitors (PIs) show large interindividual variations. It is not clear what clinical impact these differences in drug concentrations might have. In this study we explored the association between serum concentration of protease inhibitors and HIV-related disease. 130 patients on PI-containing regimen underwent PI concentration measurement in serum. The results were divided into 3 categories: high level, therapeutic level, and low level. HIV-related events (CDC category B and C) and death were prospectively recorded after the drug monitoring. The results were statistically analysed employing Cox regression. Median follow-up was 709 d, and 22 patients reached an endpoint. For the trough concentrations the hazard ratio (HR) for patients with therapeutic level vs low level was 0.63 (95% CI 0.20-1.95) and high level vs low level was 0.56 (95% CI 0.14-2.26). For the maximum concentrations the HR for therapeutic level vs low level was 1.32 (95% CI 0.48-3.62) and high level vs low level was 0.47 (95% CI 0.06-3.90). In conclusion, in this small pilot study we could not show any association between the serum concentrations of PIs and subsequent clinical HIV-related events. Larger studies are needed to explore this subject further.
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http://dx.doi.org/10.1080/00365540600616993DOI Listing
October 2006

A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial.

Antivir Ther 2005 ;10(6):735-43

Hvidovre University Hospital, Copenhagen, Denmark.

Objective: To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r).

Design: Open-label, prospective, randomized (1:1), international multi-centre trial.

Methods: Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks.

Results: Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P = 0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation = failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment (P = 0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (300%) in the SAQ/r-treated group (ITT/e; P = 0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients' choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms (P = 0.27, log rank test).

Conclusion: LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients' preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.
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November 2005

Reduced viral burden amongst high responder patients following HIV-1 p24 peptide-based therapeutic immunization.

Vaccine 2005 Jul 7;23(31):4011-5. Epub 2005 Apr 7.

Department of Infectious Diseases, Faculty Division Ullevaal University Hospital, University of Oslo, Kirkeveien 166, NO-0407 Oslo, Norway.

We have previously shown that HIV p24-like peptides (Vacc-4x) via activation of skin dendritic cells induced immune responses in 90% of HIV patients on highly active antiretroviral treatment (HAART). These patients (n=38) were here subjected to a final 14-week interruption of HAART. Patients with the highest delayed type hypersensitivity (DTH) responses to Vacc-4x-peptides before treatment interruption tended to achieve lower actual HIV RNA levels at the end of the study compared to Vacc-4x DTH low-responders (p=0.08) and significantly so in terms of viral loads relative to their individual pre-HAART HIV RNA set-points (p=0.04). CD4+ lymphocyte counts were maintained only among DTH high responders but decreased in the other patients during recurrent viremia (p
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http://dx.doi.org/10.1016/j.vaccine.2005.03.010DOI Listing
July 2005

Low prevalence of high-density lipoprotein cholesterol level < 1 mmol/L in non-nucleoside reverse transcriptase inhibitor recipients.

Int J STD AIDS 2005 May;16(5):365-9

Department of Infectious Diseases, Ullevål University Hospital, 0407 Oslo, Norway.

Our objective was to compare the prevalence of high-density lipoprotein-cholesterol (HDL-c) level < 1 mmol/L in non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) recipients in an unselected HIV-positive population. All HIV-positive patients living in Oslo who attended our outpatient clinic from April 1, 2000 to April 1, 2001 were invited to a study of cardiovascular risk factors. In this substudy, 40 NNRTI recipients and 124 PI recipients were included. Prevalence of HDL-c <1 mmol/L was 7.5% in the NNRTI recipients compared with 35.5% in the PI recipients (P <0.001). In the multivariate analyses, use of NNRTI was a significant protective factor (odds ratio [OR] 0.17; 95% confidence interval [CI] 0.05-0.66; P = 0.01) and elevated triglycerides a significant risk factor (OR 3.40; 95% CI 1.47-7.86; P = 0.004) for low HDL-c level. Our study shows that NNRTI recipients have a more favourable HDL-c profile than PI recipients, even when possible confounding factors are taken into account.
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http://dx.doi.org/10.1258/0956462053888808DOI Listing
May 2005

Divergent in vitro and in vivo correlates of HIV-specific T-cell responses during onset of HIV viraemia.

AIDS 2005 Mar;19(6):563-7

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

Background: Cellular immune responses to HIV-1 have been examined mainly in peripheral blood mononuclear cells (PBMC). During onset of HIV replication and antigenaemia after discontinuation of highly active antiretroviral therapy (HAART), PBMC may theoretically contain HIV-specific T cells that are qualitatively and quantitatively different from specific T cells dominating in the tissues. PBMC responses throughout HIV immunotherapy trials may therefore be skewed during recurrent viraemia.

Objective: To compare cellular HIV-specific in vitro responses in PBMC during onset of HIV viraemia with corresponding in vivo responses, represented by classical delayed-type hypersensitivity tests (DTH).

Methods: HIV patients (n = 38), pre-immunized with four HIV-1 p24-like consensus peptides (Vacc-4x) during HAART, were subjected to a 14-week treatment interruption with recurrent HIV viraemia. Proliferative T-cell responses to Vacc-4x p24 peptides, HIV p24 protein, and cytomegalovirus (CMV) proteins were measured in PBMC. Corresponding Vacc-4x peptide DTH were expressed as skin infiltrate areas after 48 h.

Results: After 14 weeks without HAART, HIV-1 RNA increased to 72,500 copies/ml (median). The Vacc-4x p24 peptide- and HIV-1 p24 protein-induced T-cell proliferation concurrently decreased by 81 and 93% in PBMC during viraemia (medians, P < or = 0.03), whereas proliferative responses to CMV antigens were stable. In contrast, the Vacc-4x DTH areas, rather tended to increase by 36% (P = 0.08) and contained infiltrates dominated by proliferating T cells and macrophages.

Conclusions: Divergent in vitro and in vivo HIV-specific cellular immune responses were found during recurrent HIV viraemia. The clinical relevance of both surrogate markers for HIV-related immune responses should be compared in future studies.
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http://dx.doi.org/10.1097/01.aids.0000163932.76531.c6DOI Listing
March 2005