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Interleukin-12 receptor deficiency is a well-described cause of human susceptibility to infection with low-virulent mycobacteria and Salmonella species. We identified a male patient presenting in his late forties with severe gastroenteropathy because of outbred infestation by a previously unknown mycobacterium. In addition to selective IgA deficiency, the patient was found to carry a not previously described R283X homozygous mutation in his IL12R¿1 gene. Two of his sisters, a brother, and his four children were healthy, heterozygous carriers of the mutation. In this patient, the combination of two deficiencies could promote illness. Even though the IgA deficiency in itself does not predispose to mycobacterial disease, the lack of secreted IgA may have disturbed the intestinal homoeostasis and increased the susceptibility to the low-virulent mycobacterium that the patient was not able to clear because of his IL12R deficiency. Antimycobacterial chemotherapy and interferon-¿ treatment for 2 years significantly improved his condition. This is the first description of IL12R¿1 deficiency combined with another immunodeficiency, and we suggest that combinatory defects may circumvent the otherwise low penetrance of IL12RB1 deficiency.

The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART).

The phylogeny and resistance profiles of human immunodeficiency virus type 1 (HIV-1) protease (PR) and reverse transcriptase (RT) sequences were compared among six patients with HIV-1 who had received numerous treatments. RNA and DNA fractions were obtained from concurrent blood and rectal biopsy samples. Phylogenetic trees and resistance profiles showed that the rectal mucosa and the peripheral blood mononuclear cells (PBMCs) harbored different HIV-1 strains. The resistance-associated mutations found in each strain corresponded to the treatment history of the patients. The resistance mutations acquired during earlier treatment regimens were detected in the sequences obtained from the rectal samples and in the PBMCs in several of the patients. Also, differences in the resistance profiles were observed between anatomical sites and between RNA and DNA fractions. Thus, a single sample probably will not be representative of the HIV-1 archived in different sites. Both the resistance profile and phylogeny of HIV-1 often differed in sequences obtained from RNA and DNA from the same site. These findings suggest that additional information regarding the antiviral resistance profile of the patient might be obtained by testing different anatomical sites.

Udgivelsesdato: 2011-Apr, OBJECTIVE: The association between HIV infection and the risk of venous thromboembolism (VTE) is controversial. We examined the risk of VTE in HIV-infected individuals compared with the general population and estimated the impact of low CD4 cell count, highly active antiretroviral therapy (HAART) and injecting drug use (IDU). METHODS: We identified 4333 Danish HIV-infected patients from the Danish HIV Cohort Study and a population-based age- and gender-matched comparison cohort of 43 330 individuals. VTE diagnoses were extracted from the Danish National Hospital Registry. Cumulative incidence curves were constructed for time to first VTE. Incidence rate ratios (IRRs) and impact of low CD4 cell count and HAART were estimated by Cox regression analyses. Analyses were stratified by IDU, adjusted for comorbidity and disaggregated by overall, provoked and unprovoked VTE. RESULTS: The 5-year risk of VTE was 8.0% [95% confidence interval (CI) 5.78-10.74%] in IDU HIV-infected patients, 1.5% (95% CI 1.14-1.95%) in non-IDU HIV-infected patients and 0.3% (95% CI 0.29-0.41%) in the population comparison cohort. In non-IDU HIV-infected patients, adjusted IRRs for unprovoked and provoked VTE were 3.42 (95% CI 2.58-4.54) and 5.51 (95% CI 3.29-9.23), respectively, compared with the population comparison cohort. In IDU HIV-infected patients, the adjusted IRRs were 12.66 (95% CI 6.03-26.59) for unprovoked VTE and 9.38 (95% CI 1.61-54.50) for provoked VTE. Low CD4 cell count had a minor impact on these risk estimates, while HAART increased the overall risk (IRR 1.93; 95% CI 1.00-3.72). CONCLUSION: HIV-infected patients are at increased risk of VTE, especially in the IDU population. HAART and possibly low CD4 cell count further increase the risk.

Udgivelsesdato: 2010-Apr, Acute hepatitis C virus (HCV) infection may lead to chronic HCV-infection with detectable HCV RNA or to spontaneous clearance with no HCV RNA, but detectable HCV antibodies. It is unknown whether HCV RNA status is associated with mortality in HIV-infected injection drug users (IDUs). We conducted a nationwide population-based cohort study to examine the impact of HCV RNA status on overall and cause-specific mortality in HIV-infected IDUs. We computed cumulative mortality and used Cox Regression to estimate mortality rate ratios (MRR). We identified 392 HIV-infected patients of whom 284 (72%) had chronic HCV-infection (HCV RNA positive patients) and 108 (28%) had cleared the HCV-infection (HCV RNA negative patients). During 1286 person-years of observation (PYR), 157 persons died (MR = 122/1000 PYR, 95% CI: 104-143). The estimated 5-year probabilities of survival were 0.58 (95% CI: 0.51-0.65) in the chronically HCV-infected and 0.52 (95% CI: 0.40-0.63) in the cleared HCV group. Chronic HCV-infection was not associated with overall mortality: MRR 0.85, 95% CI: 0.59-1.21. In HIV-infected Danish IDUs, chronic HCV-infection is not associated with increased mortality compared to patients who have cleared the infection.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

Udgivelsesdato: 2009

BACKGROUND: Newer antiretroviral treatment regimens for HIV carry a lower risk of inducing drug resistance mutations. We estimated changes in incidence rates (IRs) of new mutations in HIV-infected individuals receiving highly active antiretroviral therapy (HAART). METHODS: Population-based data were obtained from the Danish HIV Cohort Study and the Danish HIV Sequence Database. We included treatment-naive patients initiating HAART after December 1997 and computed time to first drug resistance mutation, identified as new mutations detected within 1 year after a 60-day period of treatment failure (HIV RNA>1,000 copies/ml). We estimated annual IRs of new resistance mutations towards nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PI), and of new specific resistance mutations. RESULTS: A total of 1,829 individuals were observed for 7,294 person-years at risk (PYR). The IR of NRTI resistance decreased from 13.1 per 1,000 PYR (95% confidence interval [CI] 4.9-35.0) in 1999 to 3.7 (1.9-7.2) in 2004-2005 (test for trend P=0.024). The IR of NNRTI resistance decreased from 15.4 (2.2-109.6) in 1999 to 7.9 (4.6-13.6) in 2004-2005 (P=0.077). The IR of PI resistance decreased from 7.5 (1.4-21.8) in 1999 to 2.9 (0.7-11.4) in 2002-2003 (P=0.148). The IRs were low for specific resistance mutations, except for M184V (IR 5.6 [4.0-7.9]) and K103N (IR 8.2 [5.6-12.0]). CONCLUSIONS: The incidence of acquired drug resistance has decreased among HIV-infected patients treated with HAART in Denmark during 1999-2005 Udgivelsesdato: 2009

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) specifically target the HIV-1 protease enzyme. Mutations in the enzyme can result in PI resistance (termed PI mutations); however, mutations in the HIV-1 gag region, the substrate for the protease enzyme, might also lead to PI resistance. We analyzed gag and pol sequence data from the following 313 HIV-1-infected patients: 160 treatment-naive patients, 93 patients failing antiretroviral treatment that included a PI (with no major PI mutations), and 60 patients failing antiretroviral treatment that included a PI (with major PI mutations). Additional sequences from 13 patients were included for longitudinal analysis. We assessed positive selection pressure on the gag/protease region using a test for the overall influence of positive selection and a total of five tests to identify positively selected single codons. We found that positive selection pressure was the driving evolutionary force for the gag region in all three patient groups. An increase in positive selection was observed in gag cleavage site regions p7/p1/p6 only after the acquisition of major PI mutations, suggesting that amino acids in gag cleavage sites under positive selection pressure could function as compensatory mutations for major PI mutations in the protease region. Isolated gag mutations did not appear to confer PI resistance, but mutations in the gag cleavage sites could substitute for minor PI resistance mutations in the protease region Udgivelsesdato: 2009/9

BACKGROUND: HIV-infected persons are at increased risk of pneumonia, even with highly active antiretroviral treatment (HAART). We examined the impact of pneumonia on mortality and identified prognostic factors for death among HIV-infected. METHODOLOGY/PRINCIPAL FINDINGS: In a nationwide, population-based cohort of individuals with HIV, we included persons hospitalized with pneumonia from the Danish National Hospital Registry and obtained mortality data from the Danish Civil Registration System. Comparing individuals with and without pneumonia, we used Poisson regression to estimate relative mortality and logistic regression to examine prognostic factors for death following pneumonia. From January 1, 1995, to July 1, 2008, we observed 699 episodes of first hospitalization for pneumonia among 4,352 HIV patients. Ninety-day mortality after pneumonia decreased from 22.4% (95% confidence interval [CI]: 16.5%-28.9%) in 1995-1996 to 8.4% (95% CI: 6.1%-11.6%) in 2000-2008. Mortality remained elevated for more than a year after hospitalization for pneumonia: adjusted mortality rate ratio 5.38 (95% CI: 4.27-6.78), 1.80 (95% CI: 1.36-2.37), and 1.62 (95% CI: 1.32-2.00) for days 0-90, 91-365, and 366+, respectively. The following variables predicted mortality within 90 days following hospitalization for pneumonia (adjusted Odds Ratios): male sex (3.77, 95% CI: 1.37-10.4), Charlson Comorbidity Index score > or = 2 (3.86, 95% CI: 2.19-6.78); no current HAART (3.58, 95% CI: 1.83-6.99); history of AIDS (2.46, 95% CI: 1.40-4.32); age per 10 year increase (1.43, 95% CI: 1.11-1.85); and CD4+ cell count < or = 200 (2.52, 95% CI: 1.37-4.65). CONCLUSIONS/SIGNIFICANCE: The first hospitalization for pneumonia among HIV-infected individuals was associated with elevated risk of death up to more than a year later. Use of HAART decreased the risk, independent of current CD4+ cell count. Prognosis following pneumonia improved over calendar time Udgivelsesdato: 2009, BACKGROUND: HIV-infected persons are at increased risk of pneumonia, even with highly active antiretroviral treatment (HAART). We examined the impact of pneumonia on mortality and identified prognostic factors for death among HIV-infected. METHODOLOGY/PRINCIPAL FINDINGS: In a nationwide, population-based cohort of individuals with HIV, we included persons hospitalized with pneumonia from the Danish National Hospital Registry and obtained mortality data from the Danish Civil Registration System. Comparing individuals with and without pneumonia, we used Poisson regression to estimate relative mortality and logistic regression to examine prognostic factors for death following pneumonia. From January 1, 1995, to July 1, 2008, we observed 699 episodes of first hospitalization for pneumonia among 4,352 HIV patients. Ninety-day mortality after pneumonia decreased from 22.4% (95% confidence interval [CI]: 16.5%-28.9%) in 1995-1996 to 8.4% (95% CI: 6.1%-11.6%) in 2000-2008. Mortality remained elevated for more than a year after hospitalization for pneumonia: adjusted mortality rate ratio 5.38 (95% CI: 4.27-6.78), 1.80 (95% CI: 1.36-2.37), and 1.62 (95% CI: 1.32-2.00) for days 0-90, 91-365, and 366+, respectively. The following variables predicted mortality within 90 days following hospitalization for pneumonia (adjusted Odds Ratios): male sex (3.77, 95% CI: 1.37-10.4), Charlson Comorbidity Index score > or = 2 (3.86, 95% CI: 2.19-6.78); no current HAART (3.58, 95% CI: 1.83-6.99); history of AIDS (2.46, 95% CI: 1.40-4.32); age per 10 year increase (1.43, 95% CI: 1.11-1.85); and CD4+ cell count < or = 200 (2.52, 95% CI: 1.37-4.65). CONCLUSIONS/SIGNIFICANCE: The first hospitalization for pneumonia among HIV-infected individuals was associated with elevated risk of death up to more than a year later. Use of HAART decreased the risk, independent of current CD4+ cell count. Prognosis following pneumonia improved over calendar time.

The introduction of antiretroviral combination therapy for patients with HIV infection is described as an example of a breakthrough within the field of medical treatment. The background for the breakthrough and the phases thereof are described and for comparison, the circumstances of major breakthroughs within other medical specialities are mentioned Udgivelsesdato: 2009/3/2

Udgivelsesdato: 2010-Feb, OBJECTIVE: The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI). DESIGN, SETTING AND SUBJECTS: This was a prospective nationwide cohort study which included all Danish HIV-infected patients on highly active antiretroviral therapy (HAART) from 1995 to 2005 (N = 2952). Data on hospitalization for MI and comorbidity were obtained from Danish medical databases. Hospitalization rates for MI after HAART initiation were calculated for patients who used abacavir and those who did not. We used Cox's regression to compute incidence rate ratios (IRR) as a measure of relative risk for MI, while controlling for potential confounders (as separate variables and via propensity score) including comorbidity. MAIN OUTCOME: Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers. RESULTS: Hospitalization rates for MI were 2.4/1000 person-years (PYR) [95% confidence interval (CI) 1.7-3.4] for abacavir nonusers and 5.7/1000 PYR (95% CI 4.1-7.9) for abacavir users. The risk of MI increased after initiation of abacavir [unadjusted IRR = 2.22 (95% CI 1.31-3.76); IRR adjusted for confounders = 2.00 (95% CI 1.10-3.64); IRR adjusted for propensity score = 2.00 (95% CI 1.07-3.76)]. This effect was also observed among patients initiating abacavir within 2 years after the start of HAART and among patients who started abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. CONCLUSIONS: We confirmed the association between abacavir use and increased risk of MI. Further studies are needed to control for potential confounding not measured in research to date.

A molecular epidemiologic study of HIV-1 in Greenland showed distinct transmission clusters correlated with demographic and behavioral data. Resistance mutations were found in a majority of the pol sequences. The objective of the present study was to estimate prevalence of drug resistance in Greenland and identify transmission chains by comparing resistance data with phylogeny and treatment history. Of 60 untreated patients, 15 (25%) had primary resistance mutations. The most prevalent mutations were T69D/N (15%), K70R (15%), and M184V (10%). Four possible transmission chains were identified based on phylogeny and mutation profiles. The clusters consisted of treated and untreated patients and showed the same mutation profiles in both resistance and nonresistance positions. Prevalence of transmitted drug resistance in Greenland (25%) is higher than in Denmark where only 3% transmission was observed. Suboptimal use of nucleoside reverse transcriptase inhibitor (NRTI) in Greenland was reflected in the high prevalence of NRTI-related resistance in the patients. A combination of phylogeny and genotypic resistance tests enabled us to study the number of transmissions and how the virus was transmitted. Resistance mutations detected in untreated patients were backed up by the treatment history of index patients in the possible transmission chains and indicated that these drug-resistant variants were in fact transmitted and had not emerged due to unregistered drug intake Udgivelsesdato: 2008/8

Analyses from the Danish HIV Cohort Study showed that, despite comparable economic means and general education of healthcare personnel, antiretroviral treatment of HIV in Greenland began later and has been implemented at a slower pace with lower therapeutic effectiveness than in Denmark. However, implementation and quality of care improved considerably in recent years Udgivelsesdato: 2008/1

BACKGROUND: Hospital-based discharge registries are used increasingly for longitudinal epidemiological studies of HIV. We examined completeness of registration of HIV infections and of chronic hepatitis B (HBV) and hepatitis C (HCV) coinfections in the Danish National Hospital Registry (DNHR) covering all Danish hospitals. METHODS: The Danish HIV Cohort Study (DHCS) encompasses all HIV-infected patients treated in Danish HIV clinics since 1 January 1995. All 2,033 Danish patients in DHCS diagnosed with HIV-1 during the 10-year period from 1 January 1995 to 31 December 2004 were included in the current analysis. We used the DHCS as a reference to examine the completeness of HIV and of HBV and HCV coinfections recorded in DNHR. Cox regression analysis was used to estimate hazard ratios of time to diagnosis of HIV in DNHR compared to DHCS. RESULTS: Of the 2,033 HIV patients in DHCS, a total of 2,006 (99%) were registered with HIV in DNHR. Of these, 1,888 (93%) were registered in DNHR within one year of their first positive HIV test. A CD4 < 200 cells/microl, a viral load > or = 100,000 copies/ml and being diagnosed after 1 January 2000, were associated with earlier registration in DNHR, both in crude and adjusted analyses. Thirty (23%) HIV patients registered with chronic HBV (n = 129) in DHCS and 126 (48%) of HIV patients with HCV (n = 264) in DHCS were registered with these diagnoses in the DNHR. Further 17 and 8 patients were registered with HBV and HCV respectively in DNHR, but not in DHCS. The positive predictive values of being registered with HBV and HCV in DHCS were thereby estimated to 0.88 and 0.97 and in DNHR to 0.32 and 0.54. CONCLUSION: The study demonstrates that secondary data from national hospital databases may be reliable for identification of patients diagnosed with HIV infection. However, the predictive value of co-morbidity data may be low Udgivelsesdato: 2008

OBJECTIVE: To compare the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients initiating equivalent regimens within and outside a randomized controlled trial (RCT). STUDY DESIGN AND SETTING: The Danish Protease Inhibitor Study (DAPIS) was a national multicenter RCT comparing initial treatment with indinavir, ritonavir, or saquinavir/ritonavir during 96 weeks. From the Danish HIV Cohort Study we identified all patients initiating one of these protease-inhibitor-based HAART regimens: 425 patients within DAPIS and 677 outside the trial. We compared viral load, CD4 count response, and mortality. RESULTS: At weeks 96 and 240, trial participants were more likely than nonparticipants to have undetectable viral load (adjusted odds ratio [adOR] 1.28 [95% CI=0.94-1.74] and 1.70 [95% CI=1.16-2.50]) and a CD4 increase > or =100 cells/microl (adOR 1.37 [95% CI=1.03-1.82] and 1.53 [95% CI=1.04-2.25]). For antiretroviral-experienced, but not for antiretroviral-naive patients, trial participants had a lower risk of death (mortality rate ratio [MRR]=0.46 [95% CI=0.27-0.77]) than nonparticipants. This effect was moderated in adjusted analyses (MRR=0.60 [0.33-1.07]). CONCLUSIONS: Compared to nontrial patients, trial participants had better response to HAART. The differences were small defying the notion that results obtained in RCTs are unachievable in routine clinical practice Udgivelsesdato: 2008/1

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals with high CD4(+) cell counts may have increased susceptibility to other infections. We compared incidence rates of pneumonia among individuals with and without HIV infection and explored risk factors for pneumonia in the HIV-infected population. METHODS: This was an observational cohort study conducted during 1995-2007. Each member of a Danish population-based nationwide cohort of HIV-infected individuals was matched with up to 99 control individuals from the general population. Data on age, mortality, emigration, and hospital discharge diagnoses from 1977 onward were obtained from nationwide administrative databases. Individuals without previous hospitalization for pneumonia were observed from the date of HIV diagnosis until the first hospitalization to treat pneumonia (excluding pneumonia attributable to Pneumocystis jiroveci). Risk factors were assessed by Poisson regression. RESULTS: The study included 3516 persons with HIV infection and 328,738 persons without HIV infection, which provided 23,677 person-years and 2,944,760 person-years of observation, respectively. Incidence rates of pneumonia in HIV-infected individuals decreased from 50.6 hospitalizations per 1000 person-years (95% confidence interval [CI], 42.9-59.7 hospitalizations per 1000 person-years) during 1995-1996 to 19.7 hospitalizations per 1000 person-years (95% CI, 16.2-23.8 hospitalizations per 1000 person-years) during 2005-2007. Compared with control individuals, incidence rate ratios were 34.6 (95% CI, 28.4-41.8) during 1995-1996; 6.3 (95% CI, 5.1-7.7) during 2005-2007; and 5.9 (95% CI, 4.2-7.6) during 2005-2007 for the subgroup with a CD4(+) cell count >500 cells/microL. Injection drug use, low current CD4(+) cell count, nadir CD4(+) cell count, increasing age, and no current receipt of highly active antiretroviral therapy increased the risk of pneumonia. CONCLUSIONS: The risk of pneumonia in persons with HIV infection ha, BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals with high CD4(+) cell counts may have increased susceptibility to other infections. We compared incidence rates of pneumonia among individuals with and without HIV infection and explored risk factors for pneumonia in the HIV-infected population. METHODS: This was an observational cohort study conducted during 1995-2007. Each member of a Danish population-based nationwide cohort of HIV-infected individuals was matched with up to 99 control individuals from the general population. Data on age, mortality, emigration, and hospital discharge diagnoses from 1977 onward were obtained from nationwide administrative databases. Individuals without previous hospitalization for pneumonia were observed from the date of HIV diagnosis until the first hospitalization to treat pneumonia (excluding pneumonia attributable to Pneumocystis jiroveci). Risk factors were assessed by Poisson regression. RESULTS: The study included 3516 persons with HIV infection and 328,738 persons without HIV infection, which provided 23,677 person-years and 2,944,760 person-years of observation, respectively. Incidence rates of pneumonia in HIV-infected individuals decreased from 50.6 hospitalizations per 1000 person-years (95% confidence interval [CI], 42.9-59.7 hospitalizations per 1000 person-years) during 1995-1996 to 19.7 hospitalizations per 1000 person-years (95% CI, 16.2-23.8 hospitalizations per 1000 person-years) during 2005-2007. Compared with control individuals, incidence rate ratios were 34.6 (95% CI, 28.4-41.8) during 1995-1996; 6.3 (95% CI, 5.1-7.7) during 2005-2007; and 5.9 (95% CI, 4.2-7.6) during 2005-2007 for the subgroup with a CD4(+) cell count >500 cells/microL. Injection drug use, low current CD4(+) cell count, nadir CD4(+) cell count, increasing age, and no current receipt of highly active antiretroviral therapy increased the risk of pneumonia. CONCLUSIONS: The risk of pneumonia in persons with HIV infection ha

INTRODUCTION: The incidence of new HIV diagnoses in Denmark has remained stable since 1991, but it has increased among the subgroup of homosexual men in recent years. This may reflect an actual increase in newly infected, e.g. as a result of increased risk behaviour, or it may reflect increased HIV testing. To clarify the causes of this increase we describe and analyse the development of HIV infection in Denmark in the period 1995-2005 with special emphasis on the route of transmission, immunological status at the time of diagnosis and the prevalence of patients at risk of transmitting HIV. MATERIALS AND METHODS: Observational study based on the Danish HIV Cohort Study, which includes all adults seen at Danish HIV clinics since 1995. RESULTS: From 2000 to 2004 the number of newly-infected homosexual men increased (from 69 to 123), particularly in persons under 30 years (from 5 to 42). The median CD4 cell count at the time of diagnosis increased in this group (median 19.1 cells/microL per year [95% CI: 3.7-11.3]), while it remained stable among heterosexually infected. The number of newly-diagnosed homosexually infected under 30 years with a CD4 cell count over 400 cells/microL increased from 0 in 2000 to 23 in 2004. The prevalence of patients with high viral load (and thus potentially at risk of transmitting HIV) decreased in all risk groups. CONCLUSION: Newly-diagnosed homosexual men present at an earlier stage of disease progression and with a better preserved immune system today than 5-10 years ago, presumably due to a combination of frequent HIV testing and increased risk behaviour among young homosexuals in particular. Increased preventive measures targeting known risk groups are necessary to prevent further spread Udgivelsesdato: 2008/2/25

Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

OBJECTIVES: To establish the prevalence and quantify the severity of body fat redistribution and dyslipidaemia in HIV-infected men after long-term highly active antiretroviral therapy (HAART) compared with the background population. METHODS: In a cross-sectional study, we included 87 HIV-infected men who had received HAART for at least 6 years and 34 HIV-negative men. Regional body composition was assessed using dual-energy X-ray absorptiometry. Fasting metabolic parameters were obtained. Associations between regional body fat distribution and metabolic parameters were evaluated. RESULTS: HIV-infected patients and controls did not differ with regard to height and lean body mass. Compared with controls, HIV-infected men had reduced total fat mass (median 12.3 versus 19.2 kg, P<0.001), limb fat mass (4.3 versus 7.9 kg, P<0.001), and trunk fat mass (6.7 versus 10.8 kg, P<0.001) and higher trunk/limb fat ratio (1.7 versus 1.2, P<0.001). Also, patients without clinical lipodystrophy had reduced amounts of limb and trunk fat. In HIV-infected men, triglyceride levels were higher (2.0 versus 1.2 mmol/L, P<0.001), high-density lipoprotein (HDL)-cholesterol levels were lower (1.2 versus 1.3 mmol/L, P<0.05) and insulin levels were higher (40.8 versus 29.9 pmol/L, P<0.01) than in controls. All adverse metabolic parameters correlated with increased trunk/limb fat ratio, and insulin levels correlated positively with trunk fat mass (P<0.01). CONCLUSION: Peripheral as well as central fat loss is a general characteristic of HIV-infected men after long-term HAART. Although lipoatrophy was the dominant morphological presentation, the adverse metabolic parameters were mainly associated with the increased ratio of trunk/limb fat.

Udgivelsesdato: 2004-Sep, OBJECTIVES: To investigate the interplay between resistance and adherence in the virological failure of three fundamentally different highly active antiretroviral therapy (HAART) regimens. METHODS: We retrospectively identified 56 verified primary virological failures (viral load >400 HIV-1 RNA copies/mL) among 293 patients randomized to two nucleoside reverse transcriptase inhibitors (NRTIs)+ritonavir+saquinavir (RS-arm) (n=115), two NRTIs+nevirapine+nelfinavir (NN-arm) (n=118), or abacavir+stavudine+didanosine (ASD-arm) (n=60) followed up for a median of 90 weeks. Data on adherence were collected from patient files, and genotyping was performed on plasma samples collected at time of failure. RESULTS: Treatment interruption or poor adherence was mainly caused by side effects and accounted for 74% of failures, and was associated with absence of resistance mutations. In the 30 failing patients not switched from randomized treatment, we found resistance in two of 12 patients in the RS-arm (M184 V only), four of six patients in the NN-arm [all four had non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations], and seven of 12 patients in the ASD-arm (NRTI mutations only). Two adherent patients on randomized treatment failed in the RS-arm, none in the NN-arm, and six in the ASD-arm. CONCLUSIONS: Primary virological failure was caused mainly by treatment interruption. No primary protease inhibitor (PI) mutations were found in patients failing on boosted saquinavir, whereas resistance to NNRTIs and NRTIs was prevalent in several patients failing on regimens based on these medications.

Tenofovir treatment in an unselected cohort of highly antiretroviral experienced HIV positive patients.Lerbaek A, Kristiansen TB, Katzenstein TL, Mathiesen L, Gerstoft J, Nielsen C, Larsen K, Nielsen JO, Obel N, Laursen AL, Nielsen SD. Department of Infectious Diseases, Hvidovre Hospital, Copenhagen, Denmark. The aim of the present study was to explore the treatment effect of tenofovir as implemented in clinical practice. Data are presented on 34 patients. 11 patients had tenofovir added to a stable anti-retroviral treatment (ART) and 23 patients had drugs other than tenofovir. CD4 counts, HIV-RNA levels and genotypic resistance were determined at baseline and after 3 and 6 months. After initiation of tenofovir treatment, a mean decrease in HIV-RNA for all 34 patients was observed (-0.43 log1o copies/ml (+/- 1.22) and -0.49 log10 copies/ml (+/- 1.36) after 3 and 6 months, respectively, (p = 0.045)). However, the effect of tenofovir on HIV-RNA in the group of patients who had tenofovir added to a stable ART was limited, and the decrease in HIV-RNA was significantly higher in patients who had drugs other than tenofovir changed as well (p = 0.004 and p = 0.03 after 3 and 6 months, respectively). After initiation of tenofovir treatment, no significant increases in CD4 count were observed. All new NRTI-associated mutations could be explained by the background treatment. In conclusion, we observed a significant decrease in HIV-RNA only when tenofovir was prescribed, in conjunction with other anti-retroviral drugs, to patients on a failing highly active antiretroviral drug regimen (HAART).

Udgivelsesdato: 2004-May, This multicentre prospective study was conducted to investigate whether the level of the soluble form of urokinase-type plasminogen activator receptor (suPAR) is elevated during pneumococcal bacteraemia and is of predictive value in the early stage of the disease. Plasma levels of suPAR were increased significantly (median 5.5; range 2.4-21.0 ng/mL) in 141 patients with pneumococcal bacteraemia, compared to 31 healthy controls (median 2.6, range 1.5-4.0 ng/mL, p 0.001). Furthermore, suPAR levels were elevated significantly in patients who died from the infection (n = 24) compared to survivors (n = 117; p < 0.001). No correlation was found between suPAR levels and C-reactive protein. In univariate logistic regression analysis, hypotension, renal failure, cerebral symptoms and high serum concentrations of protein YKL-40 and suPAR were associated significantly with mortality (p < 0.05). In multivariate analysis, only suPAR remained a significant predictor of death (mortality rate of 13 for suPAR levels of > 10 ng/mL; 95% CI: 1.1-158). The increase in suPAR levels may reflect increased expression by vascular or inflammatory cells in the setting of pneumococcal sepsis. This plasma protein may be used to identify patients who are severely ill with pneumococcal bacteraemia.