Minor protease inhibitor mutations at baseline do not increase the risk for a virological failure in HIV-1 subtype B infected patients

Background Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. Methods To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. Results We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0–1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5–1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. Conclusions The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals.

Longer prior exposure to zidovudine/lamivudine-containing combination antiretroviral therapy, age, and male gender are each associated with reduced subcutaneous adipose tissue

Whether zidovudine (AZT)-associated lipoatrophy occurrence differs by concomitant exposure to protease (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains unclear. Baseline body composition data from a randomized trial in subjects stable on first-line AZT-based therapy were used to explore this issue.

Are plasma levels valid surrogates for cellular concentrations of antiretroviral drugs in HIV-infected patients?

Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients. TPC levels were analysed by high-performance liquid chromatography with ultraviolet detection and CC by LC-MS/MS from peripheral blood mononuclear cells. The best correlations between TPC and CC were observed for nelfinavir (NFV, slope=0.93, r=0.85), saquinavir (SQV, slope=0.76, r=0.80) and lopinavir (LPV, slope=0.87, r=0.63). By contrast, TPC of efavirenz (EFV) exhibited a moderate correlation with CC (slope=0.69, r=0.58), while no correlation was found for nevirapine (NVP, slope=-0.3, r=0.1). Interindividual variability in the CC/TPC ratio was lower for protease inhibitors (coefficients of variation 76%, 61%, and 80% for SQV, NFV and LPV, respectively) than for nonnucleoside reverse transcriptase inhibitors (coefficients of variation 101% and 318%, for EFV and NVP). As routine CC measurement raises practical difficulties, well-correlated plasma concentrations (ie, NFV, SQV and LPV) can probably be considered as appropriate surrogates for cellular drug exposure. For drugs such as EFV or NVP, there may be room for therapeutic drug monitoring improvement using either direct CC determination or other predictive factors such as genotyping of transporters or metabolizing enzyme genes.

Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies

BACKGROUND: No large clinical end-point trials have been conducted comparing regimens among human immunodeficiency virus type 1-positive persons starting antiretroviral therapy. We examined clinical progression according to initial regimen in the Antiretroviral Therapy Cohort Collaboration, which is based on 12 European and North American cohort studies. METHODS: We analyzed progression to death from any cause and to AIDS or death (AIDS/death), comparing efavirenz (EFV), nevirapine (NVP), nelfinavir, idinavir, ritonavir (RTV), RTV-boosted protease inhibitors (PIs), saquinavir, and abacavir. We also compared nucleoside reverse-transcriptase inhibitor pairs: zidovudine/lamivudine (AZT/3TC), stavudine (D4T)/3TC, D4T/didanosine (DDI), and others. RESULTS: A total of 17,666 treatment-naive patients, 55,622 person-years at risk, 1,617 new AIDS events, and 895 deaths were analyzed. Compared with EFV, the adjusted hazard ratio (HR) for AIDS/death was 1.28 (95% confidence interval [CI], 1.03-1.60) for NVP, 1.31 (95% CI, 1.01-1.71) for RTV, and 1.45 (95% CI, 1.15-1.81) for RTV-boosted PIs. For death, the adjusted HR for NVP was 1.65 (95% CI, 1.16-2.36). The adjusted HR for death for D4T/3TC was 1.35 (95% CI, 1.14-1.59), compared with AZT/3TC. CONCLUSIONS: Outcomes may vary across initial regimens. Results are observational and may have been affected by bias due to unmeasured or residual confounding. There is a need for large, randomized, clinical end-point trials.

Lipid profiles for antiretroviral-naive patients starting PI- and NNRTI-based therapy in the Swiss HIV cohort study

BACKGROUND: Blood lipid abnormalities in patients on highly active antiretroviral therapy (HAART) have been associated with exposure to protease inhibitors (PIs), particularly ritonavir. First therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) leads to relatively favourable lipid profiles. We report on medium-term lipid profiles (up to 5 years) for antiretroviral-naive patients starting NNRTI- and PI-based HAART in the Swiss HIV Cohort Study. METHODS: Since April 2000, blood samples taken at visits scheduled every 6 months have been analysed for cholesterol and triglyceride concentrations. For 1065 antiretroviral-naive patients starting HAART after April 2000, we estimated changes in concentration over time using multivariate linear regression with adjustment for baseline covariates, use of lipid-lowering drugs and whether the sample was taken in a fasting state. RESULTS: Non-high density lipoprotein (HDL) cholesterol levels increase with increasing exposure to either PI- or NNRTI-based therapy, HDL cholesterol levels increase and triglyceride levels decrease with increasing exposure to NNRTI-based therapy, whereas triglyceride levels increase with increasing exposure to PI-based therapy. Between NNRTI-based therapies, there is a slight difference in triglyceride levels, which tend to increase with increasing exposure to efavirenz and to decrease with increasing exposure to nevirapine. Of the three common PI-based therapies, nelfinavir appears to have a relatively favourable lipid profile, with little change with increasing exposure. Of the other two PI therapies, lopinavir with ritonavir has a more favourable profile than indinavir with ritonavir, with smaller increases in both non-HDL cholesterol and triglycerides and an increase in HDL cholesterol. Increasing exposure to abacavir is associated with a decrease in the level of triglycerides. CONCLUSION: In general, NNRTI-based therapy is associated with a more favourable lipid profile than PI-based therapy, but different PI-based therapies are associated with very different lipid profiles. Nelfinavir appears to have a relatively favourable lipid profile. Of the two boosted PI therapies, lopinavir appears to have a more favourable lipid profile than indinavir.

CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy

BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through December 2004 [corrected] all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). For follow-up, we used the Swiss HIV Cohort Study database update of May 2007 [corrected] The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.

The use of second-generation antipsychotics and the changes in physical growth in children and adolescents with perinatally acquired HIV.

Second-generation antipsychotics (SGAs) are increasingly prescribed to treat psychiatric symptoms in pediatric patients infected with HIV. We examined the relationship between prescribed SGAs and physical growth in a cohort of youth with perinatally acquired HIV-1 infection. Pediatric AIDS Clinical Trials Group (PACTG), Protocol 219C (P219C), a multicenter, longitudinal observational study of children and adolescents perinatally exposed to HIV, was conducted from September 2000 until May 2007. The analysis included P219C participants who were perinatally HIV-infected, 3-18 years old, prescribed first SGA for at least 1 month, and had available baseline data prior to starting first SGA. Each participant prescribed an SGA was matched (based on gender, age, Tanner stage, baseline body mass index [BMI] z score) with 1-3 controls without antipsychotic prescriptions. The main outcomes were short-term (approximately 6 months) and long-term (approximately 2 years) changes in BMI z scores from baseline. There were 236 participants in the short-term and 198 in the long-term analysis. In linear regression models, youth with SGA prescriptions had increased BMI z scores relative to youth without antipsychotic prescriptions, for all SGAs (short-term increase = 0.192, p = 0.003; long-term increase = 0.350, p < 0.001), and for risperidone alone (short-term = 0.239, p = 0.002; long-term = 0.360, p = 0.001). Participants receiving both protease inhibitors (PIs) and SGAs showed especially large increases. These findings suggest that growth should be carefully monitored in youth with perinatally acquired HIV who are prescribed SGAs. Future research should investigate the interaction between PIs and SGAs in children and adolescents with perinatally acquired HIV infection.

Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the d: a: d study.

BACKGROUND The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). RESULTS A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. CONCLUSIONS Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.

Protease inhibitors to treat hepatitis C in the Swiss HIV Cohort Study: high efficacy but low treatment uptake

OBJECTIVES Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs. METHODS Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs. RESULTS Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs. CONCLUSIONS The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Report of the Second European Zebrafish Principal Investigator Meeting in Karlsruhe, Germany, March 21-24, 2012.

The second European Zebrafish Principal Investigator (PI) Meeting was held in March, 2012, in Karlsruhe, Germany. It brought together PIs from all over Europe who work with fish models such as zebrafish and medaka to discuss their latest results, as well as to resolve strategic issues faced by this research community. Scientific discussion ranged from the development of new technologies for working with fish models to progress in various fields of research such as injury and repair, disease models, and cell polarity and dynamics. This meeting also marked the establishment of the European Zebrafish Resource Centre (EZRC) at Karlsruhe that in the future will serve as an important focus and community resource for zebrafish- and medaka-based research.

Caspase 8: Mediating the effects of a novel proteasome inhibitor, NPI-0052

Targeting the proteasome with the sole FDA approved proteasome inhibitor (PI), bortezomib, has been fruitful in specific cancers. Its success has generated an interest in next-generation PIs that might have a therapeutic advantage in cancers, such as leukemia, where bortezomib monotherapy was less effective. This study focuses on a novel, clinically relevant PI, NPI-0052. Experiments show that NPI-0052 targets chymotrypsin- and caspase-like activities more potently than the trypsin-like activity in leukemia cells. NPI-0052 induced apoptosis, as determined by caspase-3 activation and DNA fragmentation. Using caspase inhibitors and caspase-8 (I9.2) or FADD (I2.1) deficient cells revealed that caspase-8 was essential for NPI-0052-induced apoptosis. NPI-0052 killed cells via a caspase-8-tBid-mitochondrial pathway, relying on caspase-8, whereas bortezomib relies on several caspases. NPI-0052 increased reactive oxygen species (ROS) levels, which contributed towards cytotoxicity since an antioxidant conferred protection. To improve the clinical efficacy of PIs, NPI-0052 was combined with epigenetic anti-cancer agents, histone deacetylase inhibitors (HDACi). NPI-0052 with MS-275 or vorinostat (FDA approved HDACi), synergistically induced apoptosis more effectively than an HDACi/bortezomib regimen in Jurkat cells. Caspase-8 and ROS contributed towards NPI-0052/HDACi cytotoxicity and caspase-8 mediated superoxide production by NPI-0052 or NPI-0052/HDACi. The proximal targets of these agents: proteasome activity and histone acetylation were examined to determine if they contributed towards synergistic effects. HDACi targeted proteasomal β subunits and corresponding catalytic activities responsible for degrading proteins. Immunoblotting showed increases in histone-H3 expression and its acetylation with NPI-0052 or NPI-0052/HDACi in Jurkat and primary cells. Importantly, the hyper-acetylation by NPI-0052 was not detected with bortezomib, suggesting that this effect may be unique to NPI-0052. An antioxidant attenuated histone-H3 expression and acetylation induced by NPI-0052 alone or with HDACi. Furthermore, the hyper-acetylation by NPI-0052 relied on caspase-8. These novel results show that a PI is eliciting classical epigenetic alterations, demonstrated by hyper-acetylation of histone-H3. This alteration was oxidant and caspase-8 dependent. Overall, results reveal that caspase-8 mediates many effects induced by NPI-0052. Data show overlapping activities by NPI-0052 and HDACi which are contributing, along with caspase-8 activation and oxidative stress, to cytotoxic interactions in leukemia cells, reinforcing the potential clinical utility of combining these two compounds. ^

Pollen profiles from 8 sediment cores from the Degersee, Southern Germany

The discovery of a neolithic pile field in the shallow water near the eastern shore of the Degersee confirmed earlier palynological and sedimentological studies stating that early man was active in the region since more than 6000 years. The already available off-site data were freshly assessed, completed by additional data from old and new cores and the interpretations revised. A common time scale for the off-site data and the on-site data was obtained by AMS dating of terrestrial macro remains of the neolithic section of off-site core De_I+De_H. The ages can thus be parallelled with AMS ages of construction timber on-site. Pollen analyses from all cores provide a further time scale. The continuously and densely sampled pollen profile of the profundal zone embracing the entire Late glacial and Holocene serves as a reference. From the Boreal onwards the relative ages are transformed by AMS ages and varve counts into calibrated and absolute. A transect cored close to the neolithic pile field across the lake marl-platform demonstrates its geological architecture in the shallow water since the Lateglacial. Studies of the microfabric of thin sections of drilled cores and of box cores from the excavations demonstrate that neolithic settlements now at 2-3,5 m water depth had been erected on lake marl freshly fallen dry, thus indicating earlier lake levels dropped by 1.5-2 m. The neolithic section of the highly resolved off-site profile in the lake=s profundal zone has laminated and calcareous zones alternating with massive ones. Assemblages of diatoms and concentrations of trace elements changing simultaneously characterise the calcareous sections as deposits of low lake levels that lasted between some 40 and more than 300 years. The ages of discovered lake shore dwellings fall into calcareous segments with low lake levels. From the end of the Upper Atlantic period (F VII) appear Secondary Forest Cycles in the beech forest, a man-made sequence of repeated vegetational development with an identical pattern: With a decrease of beech pollen appear pollen of grasses, herbs and cultural indicators. These are suppressed by the light demanding hazel and birch, those again by ash, and finally by the shade demanding beech forming a new pollen peak. Seven main Forest Cycles are identified In the upper Neolithic period each comprising some 250, 450 or 800 years. They are subdivided into subcycles that can be broken down by very dense sampling in even shorter cycles of decadal length. Farming settlers have caused minor patchy clearances of the beech-mixed-forest with the use of fire. The phases of clearance coincide with peaks of charcoal and low stands of the lake levels. The Secondary Forest Cycles and the continuous occurrence of charcoal prove a continued occupation of the region. Together with the repeated restoration of the beech climax forest they point to pulsating occupation probably associated with dynamic demography. The synchronism of the many palynological, sedimentological and archaeological data point to an external forcing as the climate that affects comprehensively all these proxies. The fluctuations of the activity of the sun as manifested in the residual d14C go largely along with the proxies. The initial clearances at the begin of the forest cycles are linked to low lake levels and negative values of d14C that point to dry and warm phases of a more continental climate type. The subcycles exist independent from climatic changes, indicating that early man acted largely independent from external forces.

Universidad y política en el postperonismo : El caso de la Universidad Nacional de La Plata y su movimiento estudiantil (1955-1966). Un estado de la cuestión

Fil: Pis Diez, Nayla. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales (UNLP-CONICET); Argentina.

Análisis de la revista Envido

Envido fue una revista de política y de ciencias sociales vinculada a la izquierda peronista universitaria. Su surgimiento, en el ambiente de las Cátedras Nacionales de la Carrera de Sociología de la Universidad de Buenos Aires, expresa un hito fundamental del proceso de politización y radicalización experimentado por la sociedad argentina entre la década del sesenta y mediados de los años setenta: la peronización de los sectores medios ligados al mundo de la cultura y a la vida universitaria. En este trabajo, nos proponemos realizar un análisis de contenido que aborde los nudos centrales de la retórica política de Envido: su revisionismo histórico centrado en la contradicción principal imperialismo-nación y en la emergencia de un movimiento de liberación nacional que entre los años cuarenta y setenta se organizó bajo las banderas del peronismo. Por otro lado, se intenta trazar los debates acerca de la universidad y del mundo de la cultura que se perfilaron en las distintas publicaciones, donde se puso en juego la denuncia de una ciencia colonizada y el esfuerzo por la creación de un conocimiento rebelde al servicio de la liberación nacional. En este punto, buscaremos rastrear en la revista los esbozos del proyecto de universidad nacional y popular que se materializó en 1973 con la intervención de Rodolfo Puiggrós en la Universidad de Buenos Aires

Pollen record and age determination of a sediment profile from Schmiechener See, Germany

Die untersuchten Schluffe und Kiese sind unter kaltzeitlichen Bedingungen in einem See mit Schwimmpflanzengesellschaften abgelagert worden. Zur Sedimentationszeit gab es in der Umgebung des Sees eine tundrenartige Vegetation, die auch Steppenarten enthielt.