Switching from a protease inhibitor-based regimen to a dolutegravir-based regimen : a randomized clinical trial to determine the effect on peripheral blood and ileum biopsies from antiretroviral therapy-suppressed human immunodeficiency virus-infected individuals

Background: Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy. Methods: Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers. Results: There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4(+) T cells in both groups (P <.01). Residual viremia in plasma decreased in the switch group (P =.03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells. Conclusions: The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4(+) T cells

Safety and preliminary efficacy of vorinostat with R-EPOCH in high-risk HIV-associated non-Hodgkin\u27s lymphoma (AMC-075)

We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL

The Effect of the Estimate of Resting Metabolic Rate on the Correlation Between Energy Expenditure as Estimated Using Self-Reports of Physical Activity and Food Intake Records in Older Adults

This study measured total daily energy expenditure (TDEE) in adults at least 50 years of age. The goal was to determine the effect of the estimate of resting metabolic rate (RMR) on the relationship between energy expenditure estimates made using (a) self-reports of physical activity and (b) food intake records. The objectives were to determine if (a) RMR estimates based on body composition, body weight, and the 111 metabolic cart were strongly related to each other, and (b) TDEE estimates based on a 7- day physical activity diary and a 7-day food intake record were more strongly related to each other when an RMR was used that was based on body composition, body weight, or the met cart. This was a three-phase study. In phases I and II, the Pearson r was computed for all combinations of methods. If r \u3e .80, the most practical method for field use was used in the next phase. Phase I: Estimated body composition using bioimpedance (BIA), skinfold (SKF), and girth. Phase II: Measured RMR using a met cart and three equations. Phase III: Computed TDEE using the self-reports. The Pearson r was computed to determine which methods of estimating RMR resulted in the strongest relationships. Forty-four older adults participated. Phase I: r = .88 for SKF, girth; r = .64 for SKF, BIA. Phase II: rs ranged from .47 to .59 between the met cart-RMR and all the other methods; rs ranged from .84 to .98 for the remaining methods. Phase III: r = .41 between the two estimates of TDEE that used a body weight -RMR; r = .59 between estimates using a met cart-RMR; and r = .58 between estimates using a body composition-RMR. Even though r = .59 and r = .58 are similar, the average individual difference between the two estimates for each participant was smaller for the metabolic cart- RMR (372 calories /day) than for the body composition-RMR (1,045 calories /day), which suggests that body composition is not as useful as a met cart when estimating TDEE for older adults. When estimating clients\u27 daily calorie needs, health professionals ought to consider using a met cart to estimate RMR and TDEE instead of other methods

Immunovirological Response to Triple Nucleotide Reverse-Transcriptase Inhibitors and Ritonavir-Boosted Protease Inhibitors in Treatment-Naive HIV-2-Infected Patients: The ACHIEV2E Collaboration Study Group

This European inter-cohort collaboration shows poorer immunological and virological responses with triple NRTI compared to PI/r-containing cART in treatment-naïve HIV-2-infected patients, regardless of baseline CD4 cell count. PI/r-containing cART should be recommended as first-line antiretroviral regimens in HIV-2 infectio

Effect of changing from first- to second- line antiretroviral therapy on renal function : a retrospective study based on data from a single health facility in Namibia

Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. Objective: Assess effects of second-line cART on renal function. Methods: Retrospective longitudinal study in patients receiving cART. Results: 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/ EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART; time spent on cART weak relationship with CrCl. Conclusion: Patients on first-line cART for several years without renal impairment may experience new onset impairment during cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline

Longitudinal Assessment Of Blood Brain Barrier Disruption In Primary Hiv Infection And Effect Of Cart Therapy

Abnormal blood brain barrier (BBB) permeability has been implicated in the neuropathogenesis of chronic HIV infection. As neurocognitive impairment can persist despite effective combination antiretroviral therapy (cART), it is possible that irreversible central nervous system (CNS) processes are initiated in early infection, before cART is typically initiated. We analyzed the natural history of BBB permeability in primary HIV infection (PHI), and the effects of cART initiated during this period. CSF:Serum albumin quotient (QAlb), a marker of BBB permeability, was measured in longitudinal observational studies of PHI. We analyzed trajectories of QAlb pre- and post-cART using mixed-effects models, and associations between QAlb and CSF neurofilament light chain (NFL), N-acetylaspartate:creatinine (NAA:Cr, a magnetic resonance spectroscopy biomarker for neuronal integrity), and neuropsychological testing. Age-adjusted QAlb was elevated in PHI vs. controls at baseline (n=106, median 91 days post infection, dpi; n=64; p=0.02). Before cART, QAlb increased over time in 84 participants with normal baseline QAlb (p=0.006), and decreased in 22 with high baseline QAlb (p=0.011). QAlb correlated at baseline and longitudinally with NFL (r=0.497, p\u3c0.001; r=0.555, p\u3c0.001) and NAA:Cr in parietal grey matter (r=-0.352, p=0.015, r=-0.387, p=0.008), but not neuropsychological performance. QAlb did not change after a median 398 days of cART initiated at 225 dpi (p=0.174). QAlb rises during early HIV, associates with neuronal injury, and does not significantly improve over a year of treatment. HIV BBB-associated neuropathogenesis may be initiated in early infection

evtree: Evolutionary Learning of Globally Optimal Classification and Regression Trees in R

Commonly used classification and regression tree methods like the CART algorithm are recursive partitioning methods that build the model in a forward stepwise search. Although this approach is known to be an efficient heuristic, the results of recursive tree methods are only locally optimal, as splits are chosen to maximize homogeneity at the next step only. An alternative way to search over the parameter space of trees is to use global optimization methods like evolutionary algorithms. This paper describes the "evtree" package, which implements an evolutionary algorithm for learning globally optimal classification and regression trees in R. Computationally intensive tasks are fully computed in C++ while the "partykit" (Hothorn and Zeileis 2011) package is leveraged for representing the resulting trees in R, providing unified infrastructure for summaries, visualizations, and predictions. "evtree" is compared to "rpart" (Therneau and Atkinson 1997), the open-source CART implementation, and conditional inference trees ("ctree", Hothorn, Hornik, and Zeileis 2006). The usefulness of "evtree" is illustrated in a textbook customer classification task and a benchmark study of predictive accuracy in which "evtree" achieved at least similar and most of the time better results compared to the recursive algorithms "rpart" and "ctree".machine learning, classification trees, regression trees, evolutionary algorithms, R

HIV-1 induces in vivo platelet activation by enhancing platelet NOX2 activity.

OBJECTIVES: HIV-1 patients show increased platelet activation, but the mechanisms involved are not completely clarified. We speculated that HIV-1 might induce in vivo platelet activation by enhancing platelet NOX2-related oxidative stress. METHODS: We measured soluble CD40 Ligand (sCD40L), a systemic marker of platelet activation, in 36 HIV-1 patients under effective combined antiretroviral therapy (cART) and in 10 naïve HIV-1 subjects. As control, 20 healthy subjects (HS) were included. Platelet oxidative stress was measured by platelet NOX2-derived peptide (sNOX2-dp), p47(phox) translocation to platelet membrane and platelet prostaglandin F2α (8-iso-PGF2α). RESULTS: sCD40L was increased both in HIV-1 naïve and cART patients compared to HS (p &lt; 0.001). Platelet sNOX2-dp and 8-iso-PGF2α were significantly higher in HIV-1 naïve subjects compared to those on cART and to HS, and both were mutually correlated (R = 0.734, p &lt; 0.001). A stepwise multivariable linear regression analysis showed that platelet sNOX2-dp (β: 0.803, p &lt; 0.001), HIV-1 infection (β: 0.146, p = 0.014) and age (β: 0.166, p = 0.001) were independently associated to sCD40L levels. CONCLUSIONS: HIV-1 infection is associated with increased platelet oxidative stress, which was related to the activation of NOX2. The independent association between platelet NOX2 activation and plasma levels of sCD40L suggest that in vivo platelet activation may be dependent upon platelet oxidative stress

Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3–10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = −0.51 versus r = −0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero–acquired HIV infection after early cART initiation and may be associated with innate immune sex differences

A SUMMARY OF Classification and Regression Tree WITH APPLICATION

Classification and regression tree (CART) is a non-parametric methodology that was introduced first by Breiman and colleagues in 1984. CART is a technique which divides populations into meaningful subgroups that allows the identification of groups of interest. CART as a classification method constructs decision trees. Depending on information that is available about the dataset, a classification tree or a regression tree can be constructed. The first part of this paper describes the fundamental principles of tree construction, pruning procedure and different splitting algorithms. The second part of the paper answers the questions why or why not the CART method should be used or not. The advantages and weaknesses of the CART method are discussed and tested in detail. Finally, CART is applied to an example with real data, using the statistical software R. In this paper some graphical and plotting tools are presented