18 research outputs found
Higher plasma drug levels in elderly people living with HIV treated with darunavir
Background The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged < 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and sideeffects in PLHIV aged < 65 years of age, with controls > 49 years of age. Methods Patients < 65 years of age and controls > 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. Results Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (<49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). Conclusions Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged < 65 years of age, compared to controls >49 years of age
Infectious endocarditis, aspects on pathogenesis, diagnosis and prognosis
The incidence of infectious endocarditis (IE) is estimated to 5.9/100.000
inhabitants and year. In recent years there has been an improvement in
prognosis mainly due to more sensitive echocardiographic methods and
surgery in the acute phase of the infection. However the mortality rate
is still between 10-20% with an even higher mortality in IE caused by
Staphylococcus aureus (SA). In this thesis some aspects of pathogenesis,
diagnosis and prognosis have been studied.
In paper I, a retrospective study started 1994 the Duke criteria were
applied to 83 patients who in 88 episodes had been examined by
transesophageal echocardiography (TEE) for IE. In 49 episodes no
treatment was given, all these episodes were classified as rejected. In
39 episodes the patients were treated, 26 definite, 11 possible and 2
rejected episodes. The Duke criteria were well adapted to use in clinical
routine and valuable both in excluding patients without IE and
identifying patients with IE.
In paper II thirty-four patients with 35 episodes of IE were followed
prospectively with repeated TEE examinations (at diagnosis, discharge and
follow-up 5 months later). The use of TEE for the diagnosis was found to
be valuable as the high sensitivity and resolution enabled the diagnosis
of small vegetations (< 5 mm) in 9/35 episodes and the identification of
indications for surgery in 8/35 at the first TEE. The size of the
vegetations decreased significantly during treatment. The repeated TEE
examinations did not detect any previously unknown complications or
influence the treatment.
In paper III, a retrospective study of the period from 1994 to 2000 the
in-hospital and longterm mortality of injecting drug-users (IDU) and
non-IDU patients was compared. In this study 195 IE episodes, 60 in IDUs
and 135 non-IDUs were included. The episodes were classified by the Duke
criteria and 145 definite episodes were analysed in detail. The
favourable prognosis in right-sided IE was confirmed with no in-hospital
mortality in 29 episodes in IDUs, and long-term mortality rate as IDUs in
general. The in-hospital mortality did not differ between IDUs and
non-IDUs but IDUs with left-sided IE had a higher long-term mortality
rate than non-IDUs with left-sided IE and IDUs with right-sided IE. This
excess mortality was explained by the poor long-term survival of operated
IDUs.
In paper IV the internalization of S aureus in endothelial cells was
studied as this might be one explanation for the difficulty in treating
IE caused by SA. In an experimental model the rate of internalization of
S aureus in cultured endothelial cells was compared to the rate in human
heart valve biopsies and umbilical cord veins. The internalization rate
into biopsies was significantly diminished by a factor 300 1000
compared to cultured cells. Furthermore we studied the role of
Fibronectin Binding Protein (FnBP) on internalization into biopsies. In
cultured endothelial cells we could confirm the vital role of FnBP for
internalization but not so in the biopsies. This raises the question if
internalization is of less importance in vivo than in vitro
Long-term efficacy and safety of atazanavir/ritonavir treatment in a real-life cohort of treatment-experienced patients with HIV type 1 infection
A total of 381 Suffolk, Ile de France, Poll Dorset, Santa Ines and
crossbred sheeps was used to investigate variability, genetic
relationship, and the efficiency of protein polymorphisms in racial
characterization and parentage tests. The genetic characterization was
done through electrophoresis and by isoelectric focusing. The
investigated loci presented 64.7% of variability. Two new alleles of
Hemoglobin, HbA1 and HbB1, were detected in Santa Ines, Suffolk and
crossbred animals. The allele M of glucose phosphate isomerase is,
probably, a genetic marker for the Suffolk breed. The values of Nei's
Diversity for the leucine amino peptidase, nucleoside phosphorilase,
hemoglobin and malic enzyme loci were higher than the others,
indicating higherspecificity in sheep breed characterization. Fisher's
test revealed that allelic frequencies were different among breeds (P
< 0.01), with the exceptions of the alleles phosphogluconate
dehydrogenase and Catalase loci (P > 0.05). This genic
differentiation was confirmed by multivariate analysis, which
dendrogram, constructed from the genetic distances, showed two main
clusters: one clusters the wool and the other the hairy breeds. In the
first cluster, two distinct subgroups are observed: one represented by
the specialized breeds Poll Dorset and Ile de France, and the other
represented by the Suffolk group, demonstrating the genetic
relationships among breeds. The efficiency of these markers to exclud
one of two possible sires was 76.7, 68.0, 61.3 and 84.8 % for the Poll
Dorset, Ile de France, Suffolk and Santa Ines breeds, respectively. The
inclusion of other markers will increase the efficiency to 100% and
will allow greater precision in investigation of paternity
Patient self-reported adherence to ritonavir-boosted darunavir combined with either raltegravir or tenofovir disoproxil fumarate/emtricitabine in the NEAT001/ANRS143 Trial
NEAT001/ANRS143 trial demonstrated noninferiority of ritonavir-boosted darunavir combined with either raltegravir (RAL + DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC + DRV/r) in HIV-positive, antiretroviral-naive adults. In post hoc analyses, however, RAL + DRV/r showed inferiority in patients with baseline CD4 <200/mm and HIV-1 RNA ≥100,000 copies per milliliter. This preplanned ancillary study was conducted to assess whether differences in adherence might explain efficacy results. Phase III, open-label, randomized, multicenter study in 15 European countries (ClinicalTrials.gov, NCT01066962). Seven hundred seventy-four participants self-reported adherence (modified AIDS Clinical Trials Group questionnaire) over 96 weeks [383 RAL + DRV/r (twice daily; 5 pills/day), 391 TDF/FTC + DRV/r (once daily; 4 pills/day)]. Primary endpoint was ≥95% versus <95% adherence to prescribed doses recorded (1) over the last 4 days or (2) on the visual analogue scale over the last 30 days. Characteristics, except age, were similar between arms; 9% had CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter. Adherence ≥95% in the last 4 days (P = 0.029) or at the visual analogue scale (P = 0.0072) was higher with TDF/FTC + DRV/r than with RAL + DRV/r. Adherence ≥95% over the last 4 days was associated with lower probability of virological failure (P = 0.015). Adherence in patients with baseline CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter was similar to the rest of the population, and not significantly associated with efficacy measures, with no significant differences between arms. Adherence was high and slightly better in the TDF/FTC + DRV/r than in the RAL + DRV/r arm. No convincing evidence was found that higher failure rate in the RAL + DRV/r arm in the subgroup with worse baseline viroimmunological status is caused by adherence differences
Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals
Objective: Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial-derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having proinflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention.
Methods: Gut microbiota profiles from a probiotics intervention were investigated and validated in a cohort of HIV-infected individuals commencing antiretroviral therapy. The PiCRUSt software was used to predict overall functional capacity of the microbiota and in-house bioinformatics to distinguish between bacteria producing hexa-acylated and penta-acylated LPS.
Results and conclusion: HIV-infected individuals with the highest ratio of proinflammatory hexa-acylated LPS to noninflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan ratio, P = 0.01), indicating a link between proinflammatory LPS, tryptophan catabolism and inflammation. After probiotics for 8 weeks, there was a decrease in Gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in Gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing noninflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared with plasma LPS captured by the existing limulus assay
Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection
Long-Term Gender-Based Outcomes for Atazanavir/Ritonavir (ATV/r)- Containing Regimens in Treatment-Experienced Patients with HIV
Dynamics of Two Separate but Linked HIV-1 CRF01_AE Outbreaks among Injection Drug Users in Stockholm, Sweden, and Helsinki, Finlandâ–¿ â€
Detailed phylogenetic analyses were performed to characterize an HIV-1 outbreak among injection drug users (IDUs) in Stockholm, Sweden, in 2006. This study investigated the source and dynamics of HIV-1 spread during the outbreak as well as associated demographic and clinical factors. Seventy Swedish IDUs diagnosed during 2004 to 2007 were studied. Demographic, clinical, and laboratory data were collected, and the V3 region of the HIV-1 envelope gene was sequenced to allow detailed phylogenetic analyses. The results showed that the Stockholm outbreak was caused by a CRF01_AE variant imported from Helsinki, Finland, around 2003, which was quiescent until the outbreak started in 2006. Local Swedish subtype B variants continued to spread at a lower rate. The number of new CRF01_AE cases over a rooted phylogenetic tree accurately reflected the transmission dynamics and showed a temporary increase, by a factor of 12, in HIV incidence during the outbreak. Virus levels were similar in CRF01_AE and subtype B infections, arguing against differences in contagiousness. Similarly, there were no major differences in other baseline characteristics. Instead, the outbreak in Stockholm (and Helsinki) was best explained by an introduction of HIV into a standing network of previously uninfected IDUs. The combination of phylogenetics and epidemiological data creates a powerful tool for investigating outbreaks of HIV and other infectious diseases that could improve surveillance and prevention
Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study
Background Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate. Methods In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per mL of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT01815736
Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial
Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity