Alex Lund Laursen

Incidence, Clinical Presentation, and Outcome of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients during the Highly Active Antiretroviral Therapy Era: A Nationwide Cohort Study

BACKGROUND Human immunodeficiency virus (HIV) infection predisposes to progressive multifocal leukoencephalopathy (PML). Here, we describe the incidence, presentation, and prognosis of PML in HIV-1-infected patients during the period before highly active antiretroviral therapy (HAART) (1995-1996) and during the early HAART (1997-1999) and late HAART (2000-2006) periods. METHODS Patients from a nationwide population-based cohort of adult HIV-1-infected individuals were included. We calculated incidence rates of PML and median survival times after diagnosis. We also described neurological symptoms at presentation and follow-up. RESULTS Among 4,649 patients, we identified 47 patients with PML. The incidence rates were 3.3, 1.8, and 1.3 cases per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2006, respectively. The risk of PML was significantly associated with low CD4(+) cell count, and 47% of cases were diagnosed by means of brain biopsy or polymerase chain reaction analysis for JC virus. The predominant neurological symptoms at presentation were coordination disturbance, cognitive defects, and limb paresis. Thirty-five patients died; the median survival time was 0.4 years (95% confidence interval [CI], 0.0-0.7) in 1995-1996 and 1.8 years (95% CI, 0.6-3.0) in both 1997-1999 and 2000-2006. CD4(+) cell count >50 cells/microL at diagnosis of PML was significantly associated with reduced mortality. CONCLUSIONS The incidence of PML in HIV-infected patients decreased after the introduction of HAART. Survival after PML remains poor. In the management of PML, the main focus should be on prophylactic measures to avoid immunodeficiency.

High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment

ABSTRACT Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

Impact of Hepatitis C Virus Coinfection on Response to Highly Active Antiretroviral Therapy and Outcome in HIV-Infected Individuals: A Nationwide Cohort Study

BACKGROUND Coinfection with hepatitis C virus (HCV) in human immunodeficiency virus (HIV) type 1-infected patients may decrease the effectiveness of highly active antiretroviral therapy. We determined the impact of HCV infection on response to highly active antiretroviral therapy and outcome among Danish patients with HIV-1 infection. METHODS This prospective cohort study included all adult Danish HIV-1-infected patients who started highly active antiretroviral therapy from 1 January 1995 to 1 January 2004. Patients were classified as HCV positive (positive HCV serological test and/or HCV PCR results [443 patients [16%]]), HCV negative (consistent negative HCV serological test results [2183 patients [80%]]) and HCV-U (never tested for HCV [108 patients [4%]]). The study end points were viral load, CD4+ cell count, and mortality. RESULTS Compared with the HCV-negative group, overall mortality was significantly higher in the HCV-positive group (mortality rate ratio, 2.4; 95% confidence interval [CI], 1.9-3.0), as was liver disease-related mortality (mortality rate ratio, 16; 95% CI, 7.2-33). Furthermore, patients in the HCV-positive group had a higher risk of dying with a prothrombin time <0.3, from acquired immunodeficiency syndrome-related disease, and if they had a history of alcohol abuse. Although we observed no difference in viral load between the HCV-positive and HCV-negative groups, the HCV-positive group had a marginally lower absolute CD4+ cell count. CONCLUSIONS HIV-HCV-coinfected patients are compromised in their response to highly active antiretroviral therapy. Overall mortality, as well as mortality from liver-related and acquired immunodeficiency syndrome-related causes, is significantly increased in this patient group.

Transmission of HIV-1 Drug-Resistant Variants: Prevalence and Effect on Treatment Outcome

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) drug resistance is an important threat to the overall success of antiretroviral therapy (ART). Because of the limited sensitivity of commercial assays, transmitted drug resistance (TDR) may be underestimated; thus, the effect that TDR has on treatment outcome needs to be investigated. The objective of this study was to investigate the prevalence of TDR in HIV-infected patients and to evaluate the significance of TDR with respect to treatment outcome by analyzing plasma viral RNA and peripheral blood mononuclear cell proviral DNA for the presence of drug resistance mutations. METHODS In a prospective study, we investigated the level of TDR in 61 patients by comparing the results of a sensitive multiplex-primer-extension approach (termed HIV-SNaPshot) that is capable of screening for 9 common nucleoside reverse-transcriptase inhibitor and nonnucleotide reverse-transcriptase inhibitor mutations with those of a commercial genotyping kit, ViroSeq (Abbott). RESULTS Twenty-two patients were found to carry mutations. More patients with TDR were identified by the HIV-SNaPshot assay than by ViroSeq analysis (33% vs 13%; [P=.015). There was no significant difference in the time from initiation of ART to virological suppression between susceptible patients and those carrying low- or high-level resistance mutations (mean +/- standard deviation, 128 +/- 59.1 vs 164.9 +/- 120.4; P=.147). Furthermore, analyses of CD4 cell counts showed no significant difference between these 2 groups 1 year after the initiation of ART (mean, 184 vs 219 cells/microL; P=.267). CONCLUSION We found the prevalence of TDR in recently infected ART-naive patients to be higher than that estimated by ViroSeq genotyping alone. Follow-up of patients after treatment initiation showed a trend toward there being more clinical complications for patients carrying TDR, although a significant effect on treatment outcome could not be demonstrated. Therefore, the clinical relevance of low-abundance resistant quasispecies in early infection is still in question.

Insulin binding and hexose transport in rat adipocytes

SummaryInsulin binding, initial velocity of [14C]methylglucose transport, uptake of [14C]deoxy-glucose and conversion of [U-14C]glucose to CO2, glyceride-glycerol and fatty acids were measured at 37 °C in adipocytes from rats of different weights (135–450 g) and therefore with different mean cell volumes (53–389 pl). Insulin binding per cell increased with increasing cell size and binding was 2.3 times higher in the largest cells than in the smallest cells with tracer alone. The difference was largely accounted for by an increase in the apparent affinity. Influx of methylglucose per cell increased with increasing cell size in the absence of insulin and remained constant as a function of cell size in its presence. The effect of insulin ranged from 11 fold in small cells to 3.5 fold in large cells. The rate of conversion of [U-14C]glucose to CO2 and lipids was about half of the rate of methylglucose transport under all conditions. In contrast, the uptake of deoxyglucose in insulin-stimulated cells decreased markedly with increasing cell size. Increasing cell size caused a small decrease in sensitivity which could be explained by a smaller amount of insulin bound per unit surface area. The results show that increasing cell size/animal weight causes changes in insulin binding which may explain changes in sensitivity. In addition, the hexose transport system is modified in a way which is not explained by changes in insulin binding. Finally, changes in deoxyglucose uptake with cell size do not parallel changes in methylglucose transport.

Impact of hepatitis B virus co‐infection on response to highly active antiretroviral treatment and outcome in HIV‐infected individuals: a nationwide cohort study

The impact of chronic hepatitis B virus (HBV) infection on viral suppression, immune recovery and mortality in HIV‐1 infected patients on highly active antiretroviral treatment (HAART) is a matter of debate. The impact of HBeAg status is unknown.

Pyogenic brain abscess, a 15 year survey

BackgroundBrain abscess is a potentially fatal disease. This study assesses clinical aspects of brain abscess in a large hospital cohort.MethodsRetrospective review of adult patients with pyogenic brain abscess at Rigshospitalet University Hospital, Denmark between 1994 and 2009. Prognostic factors associated with Glasgow Outcome Score (GOS) (death, severe disability or vegetative state) were assessed by logistic regression.Results102 patients were included. On admission, only 20% of patients had a triad of fever, headache and nausea, 39% had no fever, 26% had normal CRP and 49% had no leucocytosis. Median delay from symptom onset to antibiotic treatment was 7 days (range 0–97 days). Source of infection was contiguous in 36%, haematogenous in 28%, surgical or traumatic in 9% and unknown in 27% of cases. Abscess location did not accurately predict the portal of entry. 67% were treated by burr hole aspiration, 20% by craniotomy and 13% by antibiotics alone. Median duration of antibiotic treatment was 62 days. No cases of recurrent abscess were observed. At discharge 23% had GOS ≤3. The 1-, 3- and 12-month mortality was 11%, 17% and 19%. Adverse outcome was associated with a low GCS at admission, presence of comorbidities and intraventricular rupture of abscess.ConclusionsThe clinical signs of brain abscess are unspecific, many patients presented without clear signs of infection and diagnosis and treatment were often delayed. Decreased GCS, presence of comorbidities and intraventricular rupture of brain abscess were associated with poor outcome. Brain abscess remains associated with considerable morbidity and mortality.

Comparison of Bone and Renal Effects In HIV-infected Adults Switching to Abacavir or Tenofovir Based Therapy in a Randomized Trial

Introduction Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. Methods In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. Results Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (−1.8% and −2.5%) and week 48 (−2.1% and −2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. Conclusion Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. Trial registration Clinicaltrials.gov NCT00647244

Endothelial dysfunction, increased inflammation, and activated coagulation in HIV-infected patients improve after initiation of highly active antiretroviral therapy.

Endothelial dysfunction and inflammation have been demonstrated to be markers of cardiovascular risk. We investigated the effects of HIV infection per se and the antiretroviral treatment prescribed on the levels of risk factors of cardiovascular disease.

Loss to follow-up occurs at all stages in the diagnostic and follow-up period among HIV-infected patients in Guinea-Bissau: a 7-year retrospective cohort study

Objectives To describe loss to follow-up (LTFU) at all stages of the HIV programme. Design A retrospective cohort study. Setting The HIV clinic at Hospital National Simão Mendes in Bissau, Guinea-Bissau. Participants A total of 4080 HIV-infected patients. Outcome measures Baseline characteristics, percentages and incidence rates of LTFU as well as LTFU risk factors at four different stages: immediately after HIV diagnosis (stage 1), after the first CD4 cell count and before a follow-up consultation (stage 2), after a follow-up consultation for patients not eligible for antiretroviral treatment (ART; stage 3) and LTFU among patients on ART (stage 4). Results Almost one-third of the patients were lost to the programme before the first consultation where ART initiation is decided; during the 7-year observation period, more than half of the patients had been lost to follow-up (overall incidence rate=51.1 patients lost per 100 person-years). Age below 30 years at inclusion was a risk factor for LTFU at all stages of the HIV programme. The biggest risk factors were body mass index <18.5 kg/m2 (stage 1), male gender (stage 2), HIV-2 infection (stage 3) and CD4 cell count <200 cells/μL (stage 4). Conclusions In this study, LTFU constituted a major problem, and this may apply to other similar ART facilities. More than half of the patients were lost to follow-up shortly after enrolment, possibly implying a high mortality. Thus, retention should be given a high priority.