Treatment simplification in HIV-infected adults as a strategy to prevent toxicity, improve adherence, quality of life and decrease healthcare costs

Since the advent of highly active antiretroviral therapy (HAART), the treatment of human immunodeficiency virus (HIV) infection has become more potent and better tolerated. While the current treatment regimens still have limitations, they are more effective, more convenient, and less toxic than regimens used in the early HAART era, and new agents, formulations and strategies continue to be developed. Simplification of therapy is an option for many patients currently being treated with antiretroviral therapy (ART). The main goals are to reduce pill burden, improve quality of life and enhance medication adherence, while minimizing short- and long-term toxicities, reducing the risk of virologic failure and maximizing cost-effectiveness. ART simplification strategies that are currently used or are under study include the use of once-daily regimens, less toxic drugs, fixed-dose coformulations and induction-maintenance approaches. Improved adherence and persistence have been observed with the adoption of some of these strategies. The role of regimen simplification has implications not only for individual patients, but also for health care policy. With increased interest in ART regimen simplification, it is critical to study not only implications for individual tolerability, toxicity, adherence, persistence and virologic efficacy, but also cost, scalability, and potential for dissemination and implementation, such that limited human and financial resources are optimally allocated for maximal efficiency, coverage and sustainability of global HIV/AIDS treatment

Flavin Monooxygenase-Generated N-Hydroxypipecolic Acid Is a Critical Element of Plant Systemic Immunity

Hartmann M, Zeier T, Bernsdorff F, et al. Flavin Monooxygenase-Generated N-Hydroxypipecolic Acid Is a Critical Element of Plant Systemic Immunity. Cell. 2018;173(2):456-469.e16.Following a previous microbial inoculation, plants can induce broad-spectrum immunity to pathogen infection, a phenomenon known as systemic acquired resistance (SAR). SAR establishment in Arabidopsis thaliana is regulated by the Lys catabolite pipecolic acid (Pip) and flavin-dependent-monooxygenase1 (FMO1). Here, we show that elevated Pip is sufficient to induce an FMO1-dependent transcriptional reprogramming of leaves that is reminiscent of SAR. In planta and in vitro analyses demonstrate that FMO1 functions as a pipecolate N-hydroxylase, catalyzing the biochemical conversion of Pip to N-hydroxypipecolic acid (NHP). NHP-systemically accumulates in plants after microbial attack. When exogenously applied, it overrides the defect of NHP-deficient fmo1 in acquired resistance and acts as a potent inducer of plant immunity to bacterial and oomycete infection. Our work has identified a pathogen-inducible L-Lys catabolic pathway in plants that generates the N-hydroxylated amino acid NHP as a critical regulator of systemic acquired resistance to pathogen infection

Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting.

In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure

The effect of highly active antiretroviral therapy on Human Papilloma Virus Infection and Cervical Dysplasia in women living with HIV

Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Title The Effect of Highly Active Antiretroviral Therapy on Human Papilloma Virus Infection and Cervical Cytological Abnormalities in Women Living With HIV Background Human Papillomavirus (HPV) infection causes cervical cancer. The prevalence of HPV-related dysplastic lesions is significantly higher in patients co-infected with the HI virus and thought to be linked to possible more persistent HPV infection. There is, however, conflicting evidence as to whether treatment of Human Immunodeficiency Virus (HIV) infection with antiretroviral agents may influence cervical HPV infection and the behaviour of Squamous Intraepithelial Lesions (SIL). Aims To examine the effect of the initiation of combination antiretroviral therapy (cART) on: 1) the persistence of cervical Low-grade SIL (LSIL); 2) The progression of cervical LSIL to High-Grade SIL (HSIL); 3) The effectiveness of excision treatment of HSIL 4) HPV genotypes detected, in HIVinfected and uninfected women at the Infectious Diseases Clinic and the Colposcopy Clinic, Tygerberg Teaching Hospital, Cape Town, South Africa. Design and Methods We conducted a retrospective cohort analysis of 1720 women with LSIL of the survival of progression-free-time or time-to-clearance. Time to progression or persistence was compared according to HIV status, antiretroviral treatment and CD4 count. In another retrospective cohort analysis, we investigated the effectiveness of excision treatment in 1848 women who underwent LLETZ or CKC biopsy was used. Logistic regression and survival analysis were used to compare excision treatment failure and recurrence-free time between groups according to HIV status, antiretroviral therapy and CD4 count. To investigate the effect of antiretroviral therapy on the cervical HPV infection, 300 HIV-infected women were prospectively enrolled and followed at 6-monthly interval. Cytological testing and cervical HPV sampling were done at each visit. Biopsy of suspicious lesions and excision treatment were done at colposcopy clinic according to standard a protocol. The Roche Linear array HPV genotyping test was used for HPV detection. Generalized Estimating Equation (GEE) multivariate analysis was applied to investigate the effect of cART on the detection of HPV infection, while adjusting for time-dependent covariates such as CD4 count, sexual activity and excision treatment. The effect on each HPV type was then also compared to the effect on HPV16. Results Overall, we found that there was no difference between the progression of LSIL to HSIL by HIV status. However, among HIV-infected patients, those who started ART before first LSIL had a significantly lower risk for progression (HR 0.66, 95% CI 0.54-0.81). CD4 count did not have an impact on the risk for progression. We also found lower persistence of SIL in the HIV uninfected group (HR 0.69, 95% CI 0.57-0.85) and that cART was independently associated with decreased persistence of LSIL. On the other hand, a higher CD4 count at the time of first LSIL was not associated with lower persistence of the lesion. HIV infected women with HSIL experienced much higher excision treatment failure than uninfected women (53.8% vs. 26.9%, p<0.001). Factors that improved outcome were higher CD4 count and complete excision. cART reduced the risk of detection of any HPV type by 47% (OR 0.53, 95% 0.49-0.58, p<001). When adjusted for covariates, time of exposure to cART and CD4 had a stronger effect. Every month of cART exposure reduced the risk detection of any HPV type with 7%. The effect was also significant on HPV16 alone (OR 0.93, 95% CI 0.90-0.95). All non-oncogenic subtypes were influenced similarly or more strongly than HPV16, as well as oncogenic HPV52. Only one oncogenic subtype HPV subtype, HPV39, was influenced marginally less (ratio of OR 0.95, CI 0.90-0.99, p=0.04). There was an increased risk for any HPV detection at CD4 count<200 (OR 1.63, 95% CI:1.50-1.77), but when adjusted, the time of cART exposure again remained the strongest predictor of risk (OR 0.94, 95% CI:0.93-0.95). Conclusion cART impact the outcome of cervical HPV infection by increasing clearance, decreasing progression of LSIL and recurrence after excision treatment. This effect is time dependent and also associated with CD4 count. Specifically, HPV16 detection risk is also reduced by cART, and all HPV types are influenced at least as much as HPV16, except possibly HPV39. It seems that increased cervical HIVproviral load is associated with HPV detection risk, and both are lowered by cART time.AFRIKAANSE OPSOMMING: Titel Die Effek van Kombinasie Antiretrovirale Terapie op Menslike Papilloomvirusinfeksie en Servikale Sitologiese Abnormaliteite in Menslike Immuniteitsgebrekvirus-geïnfekteerde Vroue Agtergrond Menslike Papilloomvirusinfeksie (MPV) veroorsaak servikale kanker. Die prevalensie van MPVverwante displastiese letsels is betekenisvol hoër in pasiënte wie ook met Menslike Immuniteitsgebrekvirus (MIV) geïnfekteer is en dit word gereken dat dit te wyte is aan meer persisterende MPV infeksie. Daar is egter teenstrydige bewyse oor of die behandeling van MIV infeksie met antiretrovirale (ART) middels die infeksie met MPV en die gedrag van Plaveisel Intraepiletiële letsels (PIL) kan beïnvloed. Doelwitte Om die effek van die inisiasie van kombinasie ART op: 1) die persistering van Laegraadse PIL (LPIL); 2) die progressie van servikale LPIL na hoëgraadse PIL (HPIL) 3) die sukses van eksisiebehandeling van HPIL; 4) MPV genotypies waarneembaar, in MIV-geïnfekteerde vroue by die Infeksiesiektekliniek en die Kolposkopiekliniek,Tygerberghospitaal, Kaapstad, Suid-Afrika, te ondersoek. Studie-ontwerp en Metodes `n Retrospektiewe kohort-analise op 1720 vroue met LPIL van die oorlewing van progressive-vrye tyd en tyd tot opklaring van PIL is gedoen. Tyd tot progressie of opklaring is vergelyk na aanleiding van die pasiënt se MIV status, behandeling met antiretrovirale terapie en CD4-telling. In nog `n retrospektiewe kohort-analise is die effektiwiteit van eksisiebehandeling in 1848 vroue wie LLETZ or Kouemeskonus eksisie ondergaan het, ondersoek. Logistiese regressie en oorlewingsanalise is toegepas om die voorkoms van onsuksesvolle uitkoms en tyd sonder herhaling van letsels tussen groepe te vergelyk na aanleiding van MIV status, ART en CD4-telling. Om die effek van antiretroviral therapie op servikale MPV infeksie te ondersoek, is 300 MIVgeïnfekteerde vroue opgeneem in `n prospektiewe studie en sesmaandeliks opgevolg. Sitologiese en MPV servikale smere is met elke besoek geneem. Biopsies van verdagte letsels en eksisiebehandeling is by die Kolposkopiekliniek gedoen volgens die standaardpraktyk. Die Roche Linear Array HPV Genotyping toets is gebruik vir MPV deteksie. Algemeen-beraamde vergelyking (GEE) meerveranderlike analise is toegepas om die effek van die anti-MIV terapie op die teenwoordigheid van MPV op die serviks te ondersoek. Die aangepaste effek is ook getoets deur die CD4-telling, die seksuele aktiwiteits- en eksisiebehandelingstatus by elke besoek in ag te neem. Die effek op elke MPV genotipe is laastens dan ook vergelyk met die effek op ‘n spesifieke basislyn genotype; in hierdie geval was MPV16 gekies. Resultate Daar was geen statisties beduidende verskil tussen die progressie van LPIL na HPIL na aanleding van HIV status nie, maar pasiënte wie met ART begin het voordat hulle vir die eerste keer met LPIL gediagnoseer was, het ‘n laer risiko gehad vir progressie (HR 0.66, 95% VI 0.54-0.81). Daar is ook gevind dat dit onafhanklik van die CD4 telling was. Die persistering van PIL was laer in die MIV negatiewe groep (HR 0.69, 95% VI 0.57-0.85), maar ook hier was antiretrovirale behandeling geassosieer met verminderde persistering. Weer eens was daar nie ‘n verband met die CD4 telling nie. MIV-geinfekteerde vroue met HPILwas baie meer geneig tot gefaalde eksisiebehandeling (53.8% teenoor 26.9%, p<0.001). Verbeterde uitkoms was geassosieer met ‘n hoër CD4-telling en ‘n eksisie wat as volledig beskryf was. ART wat reeds voor die eksisiebehandeling begin was, het nie die risiko vir onsuskesvolle uitkoms statisties beduidend verminder nie, maar het egter die risiko vir herhaling van letsels na die eksisie sterk verlaag. ART het die kans dat enige MPV tipe waargeneem sou word, met 47% verlaag (OR 0.53, 95% VI 0.49-0.58, p<001). Wanneer aangepas vir ander faktore, was die tyd wat verloop het sedert ART begin was, sowel as vir die CD4 telling, sterker. Vir elke maand sedert ART begin was, het die kans dat enige MPV tipe waargeneem word, met 7% verminder. `n Soortgelyke effek is op HPV16 alleen gevind (OR 0.93, 95%, VI 0.90-0.95). Die effek was net so sterk of sterker op alle subtipes. Slegs een onkogeniese subtipe, MPV39, was gering minder beïnvloed (ratio van OR 0.95, VI 0.90-0.99, p=0.04). Die kans vir waarneming van enige MPV subtype is hoër wanneer die CD4 telling laer as 200 selle/ɥl is (OR 1.63, 95% VI: 1.50-1.77), maar wanneer aangepas, was die tyd van ART weer eens die sterkste voorspeller van MPV infeksie (OR 0.94, 95% VI:0.93-0.95). Gevolgtrekkings ART verbeter die uitkoms van servikale infeksie met MPV deur progressie en persistering van LPIL en herhaling van PIL na eksisie te verminder. Die effek is tydsafhanklik en word ook deur die CD4 telling beïnvloed. Die kanse dat MPV16 spesifiek waargeneem word, word ook deur ART verminder, en all MPV tipes ondervind dieselfde of groter verlaging van waarnemingsrisiko as MPV16, behalwe miskien MPV39. Ons kon aandui dat verhoogde teenwoordigheid van servikale MIV verband hou met die risiko vir die waarneming van MPV infeksie, en beide word verminer deur die tyd waarmee die pasiënt met ARV terapie behandel is

Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy

The original publication is available at http://www.samj.org.zaENGLISH ABSTRACT: No abstract availableAFRIKAANSE OPSOMMING: Geen opsomming beskikbaarPublisher’s versio

Script-based Reappraisal Test - Introducing a new paradigm to investigate the effect of reappraisal inventiveness on reappraisal effectiveness

The ability to regulate emotions is essential for psychological well-being. Therefore, it is particularly important to investigate the specific dynamics of emotion regulation. In a new approach, we developed a novel paradigm – the Script-based Reappraisal Test (SRT) – to measure the processes involved in reappraisal, especially reappraisal inventiveness, i.e. the ability to create multiple and differing reappraisals. The aim of this study was twofold: (1) experimentally validate the SRT and (2) investigate whether reappraisal inventiveness increases reappraisal effectiveness. Healthy students (N = 143) completed the SRT. In this task, we presented everyday emotional situations in textual form and instructed participants to either decrease negative emotions by generating different reappraisals (reappraisal-trials) or react naturally (control-trials) to the situations. After each trial, participants indicated their affective state (SAM) and typed in their reappraisal thoughts. Within-subjects analyses showed significantly less negative affect and arousal in reappraisal-trials compared to control-trials, indicating a successful emotion regulation through reappraisal. Contrary to our hypothesis, reappraisal inventiveness and reappraisal effectiveness were not related. The theoretical and practical implications are discussed in the light of a person-by-situation approach

It's worth the trouble: Stressor exposure is related to increased cognitive reappraisal ability

Recent theories propose moderate (compared to high or no) stressor exposure to promote emotion regulation capacities. More precisely, stressful situations are expected to serve as practice opportunities for cognitive reappraisal (CR), that is, the reinterpretation of a situation to alter its emotional impact. Accordingly, in this study, we expect an inverted U-shaped relationship between exposure to daily hassles and performance in a CR task, that is, best reappraisal ability in individuals with a history of moderate stressor exposure. Participants (N = 165) reported the number of daily hassles during the last week as indicator of stressor exposure and completed the Script-based Reappraisal Test (SRT). In the SRT, participants are presented with fear-eliciting scripts and instructed to either downregulate negative affect via reappraisal (reappraisal-trials) or react naturally (control-trials). Two measures indicate CR ability: (1) reappraisal effectiveness, that is, the difference between affective ratings in reappraisal- and control-trials and (2) reappraisal inventiveness, that is, the number of valid and categorically different reappraisal thoughts. Multiple regression analyses revealed positive linear, but not quadratic, relationships of exposure to daily hassles and both indicators of CR ability. Potential benefits of stressor exposure for emotion regulation processes are discussed

Cognitive emotion regulation withstands the stress test:An fMRI study on the effect of acute stress on distraction and reappraisal

Cognitive emotion regulation is a key mechanism for the maintenance of mental health, but may fail, when individuals are exposed to acute stress. To date, it is not well understood whether and to what extent acute stress effects contribute to impairments in emotion regulation capacities as the sparse existing studies have yielded heterogeneous results, indicating that stress timing might be a crucial factor. In the present study, 81 healthy participants underwent either an acute stress task (ScanSTRESS-C; n = 40) or a control condition (n = 41) while lying in the MRI scanner. In the subsequent Cognitive Emotion Regulation Task (CERT), participants were confronted with neutral or negative pictures and instructed to either view them, or regulate their upcoming emotions using either distraction or reappraisal. Subjective ratings of affective state as well as functional brain imaging data served to indicate emotion regulation. The results showed a successful stress manipulation as indicated by group differences in subjective wellbeing, saliva cortisol concentrations, heart rate, and functional brain activity in regions implicated in stress processing. With respect to emotion regulation, CERT data revealed a significant regulation effect at the neural and behavioral level (less negative emotional ratings after reappraisal and distraction trials compared to view trials) in both groups. However, no significant group differences were observed, neither in BOLD responses to the CERT, nor in behavioral ratings. Contrary to previous studies, our study did not reveal further evidence of stress-related effects on emotion regulation, potentially being related to differences between studies in experimental setting, timing, and procedures. This study therefore underlines the need of future studies that disentangle the complex interplay of stress and emotion regulation and identify different factors influencing their bidirectional relationship

Investigating individual stress reactivity: High hair cortisol predicts lower acute stress responses

Identifying individual differences in stress reactivity is of particular interest in the context of stress-related disorders and resilience. Previous studies already identified several factors mediating the individual stress response of the hypothalamus-pituitary-adrenal axis (HPA). However, the impact of long-term HPA axis activity on acute stress reactivity remains inconclusive. To investigate associations between long-term HPA axis variation and individual acute stress reactivity, we tested 40 healthy volunteers for affective, endocrine, physiological, and neural reactions to a modified, compact version of the established in-MR stress paradigm ScanSTRESS (ScanSTRESS-C). Hair cortisol concentrations (HCC) served as an integrative marker of long-term HPA axis activity. First, the ScanSTRESS-C version proved to be valid in evoking a subjective, endocrine, physiological, and neural stress response with enhanced self-reported negative affect and cortisol levels, increased heart rate as well as increased activation in the anterior insula and the dorso-anterior cingulate cortex (dACC). Second and interestingly, results indicated a lower neuroendocrine stress response in individuals with higher HCC: HCC was negatively correlated with the area under the curve (respect to increase; AUCi) of saliva cortisol and with a stress-related increase in dACC activity. The present study explicitly targeted the relationship between HCC and acute stress reactivity on multiple response levels, i.e. subjective, endocrine and neural stress responses. The lower stress reactivity in individuals with higher HCC levels indicates the need for further research evaluating the role of long-term HPA axis alterations in the context of vulnerability or immunization against acute stress and following stress-related impairments