Summary Background In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for ...antiretroviral treatment. We present the 96 week results. Methods SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov , NCT01227824. Findings Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 5% patients for dolutegravir vs 43 10% patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. Interpretation At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. Funding ViiV Healthcare.
Subclinical acute ischaemic lesions on brain magnetic resonance imaging have recently been described in spontaneous intracerebral haemorrhage, and may be important to understand pathophysiology and ...guide treatment. The underlying mechanisms are uncertain. We tested the hypothesis that ischaemic lesions are related to magnetic resonance imaging markers of the severity and type of small-vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy) in a multicentre, cross-sectional study. We studied consecutive patients with intracerebral haemorrhage from four specialist stroke centres, and age-matched stroke service referrals without intracerebral haemorrhage. Acute ischaemic lesions were assessed on magnetic resonance imaging (<3 months after intracerebral haemorrhage) using diffusion-weighted imaging. White matter changes and cerebral microbleeds were rated with validated scales. We investigated associations between diffusion-weighted imaging lesions, clinical and radiological characteristics. We included 114 patients with intracerebral haemorrhage (39 with clinically probable cerebral amyloid angiopathy) and 47 age-matched controls. The prevalence of diffusion-weighted imaging lesions was 9/39 (23%) in probable cerebral amyloid angiopathy-related intracerebral haemorrhage versus 6/75 (8%) in the remaining patients with intracerebral haemorrhage (P = 0.024); no diffusion-weighted imaging lesions were found in controls. Diffusion-weighted imaging lesions were mainly cortical and were associated with mean white matter change score (odds ratio 1.14 per unit increase, 95% confidence interval 1.02-1.28, P = 0.024) and the presence of strictly lobar cerebral microbleeds (odds ratio 3.85, 95% confidence interval 1.15-12.93, P = 0.029). Acute, subclinical ischaemic brain lesions are frequent but previously underestimated after intracerebral haemorrhage, and are three times more common in cerebral amyloid angiopathy-related intracerebral haemorrhage than in other intracerebral haemorrhage types. Ischaemic brain lesions are associated with white matter changes and cerebral microbleeds, suggesting that they result from an occlusive small-vessel arteriopathy. Diffusion-weighted imaging lesions contribute to the overall burden of vascular-related brain damage in intracerebral haemorrhage, and may be a useful surrogate marker of ongoing ischaemic injury from small-vessel damage.
The vasculature of the brain and kidneys are similarly vulnerable to hypertension, so their microvascular damage may be correlated. We investigated the relationship of renal function to the ...anatomical distribution of cerebral microbleeds (CMBs), a marker of underlying cerebral small vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy), in a Western patient cohort. This was a retrospective study of referrals to a hospital stroke service. All patients with clinical data and a
T
2*-weighted gradient-recalled echo (
T
2*-GRE) MRI were included. MRI scans were rated for CMBs using the Microbleed Anatomical Rating Scale. Renal function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula. We included 202 patients, 39 with CMBs (19.3 %); 15 had “strictly lobar”, 12 had “strictly deep” and 12 had “mixed” CMBs. Patients without CMBs had a higher eGFR than those with CMBs (mean difference 6.50 ml/min/1.73 m
2
, 95 % CI −14.73 to 1.72 ml/min/1.73 m
2
,
p
= 0.121). Multivariable analysis found that those with deep and mixed CMBs had a lower eGFR than those without CMBs (mean difference −10.70 ml/min/1.73 m
2
, 95 % CI −20.35 to −1.06 ml/min/1.73 m
2
,
p
= 0.030). There was no difference in eGFR found between those with strictly lobar CMBs and those without CMBs (mean difference −1.59 ml/min/1.73 m
2
, 95 % CI −13.08 to 9.89 ml/min/1.73 m
2
,
p
= 0.79). In a Western patient cohort, there appears to be an association between eGFR and the presence of deep and mixed CMBs, but not strictly lobar CMBs. This suggests a shared vulnerability of renal afferent and cerebral deep and superficial perforating arterioles to systemic hypertension. The arteriopathy underlying strictly lobar CMBs (i.e. cerebral amyloid angiopathy), appears to be less related to renal impairment.
Commentary on the United Nations (UN) reform efforts of 2004–05 has broadly followed two different trajectories. International lawyers and political theorists have focused on the implications of ...reform for sovereignty as a fundamental principle of international law and international relations. International Relations (IR) scholars have discussed reform focusing on state power and the UN’s institutional authority. Against the background of these debates and drawing on Foucault’s political theory and related IR scholarship, this article argues that UN reform discourse indicates a biopolitical ‘reprogramming’ of contemporary sovereignty and global governance. The analysis ‘displaces’ the concerns with sovereignty, state power, and institutional authority by demonstrating that UN reform (also) constitutes the UN as a project of managing and regulating the global population through a variety of securitizing, economizing, and normalizing rationalities and techniques. The article illustrates this by pointing to the biopolitical rationales of reform conceptions of human security and collective security, and to (neo)liberal governmentalities of risk and responsibility, contractualism, benchmarking, and networks. It thereby challenges the conceptual and normative priority accorded to juridical sovereignty in international law, and to state- and institution-centric accounts in IR theorizations of UN-relayed global governance.
In untreated HIV infection, the efficacy of T cell responses decreases over the disease course, resulting in disease progression. The reasons for this development are not completely understood. ...However, immunosuppressive cells are supposedly crucially involved. Treatment strategies to avoid the induction of these cells preserve immune functions and are therefore the object of intense research efforts. In this study, we assessed the effect of treatment intensification =5-drug antiretroviral therapy (ART) on the development of suppressive cell subsets. The New Era (NE) study recruited patients with primary HIV infection (PHI) or chronically HIV-infected patients with conventional ART (CHI) and applied an intensified 5-drug regimen containing maraviroc and raltegravir for several years. We compared the frequencies of the immune suppressive cells, namely, the myeloid-derived suppressor cells (MDSCs), regulatory B cells (Bregs), and regulatory T cells (Tregs), of the treatment intensification patients to the control groups, especially to the patients with conventional 3-drug ART, and analyzed the Gag/Nef-specific CD8 T cell responses. There were no differences between PHI and CHI in the NE population (
> 0.11) for any of the studied cell types. Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic myeloid-derived suppressor cell (M-MDSC), and the Breg frequencies were comparable to those of patients with a 3-drug ART. However, the Treg levels were significantly lower in the NE patients than those in 3ART-treated individuals and other control groups (
≤ 0.0033). The Gag/Nef-specific CD8 T cell response was broader (
= 0.0134) with a higher magnitude (
= 0.026) in the NE population than that in the patients with conventional ART. However, we did not find a correlation between the frequency of the immune suppressive cells and the interferon-gamma
CD8 T cell response. In the treatment intensification subjects, the frequencies of the immune suppressive cells were comparable or lower than those of the conventional ART-treated subjects, with surprisingly broad HIV-specific CD8 T cell responses, suggesting a preservation of immune function with the applied treatment regimen. Interestingly, these effects were seen in both treatment intensification subpopulations and were not attributed to the start of treatment in primary infection.
While `world opinion' is a staple in political discourse, the concept has received
little attention in IR. Locating it along the `realist—idealist' divide,
existing studies have conceptualized `world ...opinion' empirically, as an aggregative
or intersubjective phenomenon, annexed or opposed to state sovereignty, and
embodying a normative standard. Drawing on Luhmann's conception of public opinion
and Foucault's governmentality approach, this article reconceptualizes `world
opinion' discursively (functionally and semantically), as a medium of communication
that enables post-sovereign forms of international governance irrespective of an
inherent normativity. The alternative conception of `world opinion' is illustrated
in the discourse of the emerging United Nations in the early 1940s. In this context,
`world opinion' addressed problems concerning the failure of the League of Nations,
total war, and threats to `civilization'. With public opinion research as a
technical backdrop, `world opinion' underwrote governmentalities of international
policing, welfare and rights liberalism, post-colonial pastoralism, and pedagogical
panopticism in response to these problems.
Background: Long-acting (LA) injectable antiretroviral therapy (ART) is a novel modality currently under development as an alternative to daily oral ART.
Objective: The LATTE-2 study ...(ClinicalTrials.gov identifier NCT02120352) showed that cabotegravir LA + rilpivirine LA maintained virologic suppression through 96 weeks and included further exploration of patient-reported treatment outcomes with an LA injectable form of treatment.
Methods: Two-hundred and eighty-six virologically suppressed participants on oral cabotegravir + abacavir/lamivudine once-daily tablets (induction period) were randomized to cabotegravir LA + rilpivirine LA once every 4 weeks (n = 115), once every 8 weeks (n = 115), or the continuation of the oral tablet regimen (n = 56) during the maintenance period. Patient-reported outcome measures included the HIV Medications Questionnaire (HIVMQ) and the HIV Treatment Satisfaction Questionnaire status (HIVTSQs) and change (HIVTSQc) versions at prespecified study visits through Week 96 of the randomized maintenance period.
Results: Most participants in the LA injectable groups reported injection-site-related adverse events; however, participants in the 4-week (median HIVTSQs total score, 63.5; post hoc P = 0.02) and 8-week (65.0; post hoc P < 0.001) LA injectable groups were significantly more satisfied with treatment than participants in the oral maintenance group (60.0) at Week 96. This was consistent with results from the HIVTSQc at Week 32, which revealed that participants in both LA groups were significantly more satisfied with therapy compared with patients receiving oral ART (both post hoc P < 0.001).
Conclusion: Participants who received LA injectable therapy had high levels of treatment satisfaction and favorably viewed convenience and lifestyle-related aspects of the therapy.
Risk factors for bone loss in HIV patients might differ or have a different impact in African descent compared to Caucasian populations. The aim of the paper is to analyze the relevance of risk ...factors on surrogate markers of bone metabolism in HIV-infected African descent and Caucasian patients. This is a cross-sectional study in a single HIV-specialized research and clinical care center in Munich, Germany. We included 889 patients in the study, among them 771 Caucasians (86.7%). Only in Caucasians lower vitamin D levels OR: 2.5 (95CI: 1.6-3.7), lower calcium levels OR: 1.8 (1.2-2.8), and the use of tenofovir disoproxil fumarate OR: 2.8 (1.8-4.4) were significantly associated with elevated PTH in multivariate analysis. Likewise, only in Caucasians elevated PTH was significantly associated with elevated markers of c-terminal telopeptides of collagen type 1 (β-CTX) OR: 1.7 (1.0-3.0). Effects of traditional risk factors for secondary hyperparathyroidism and increased markers of bone turn-over seem to be less distinct in African descent HIV patients. The clinical impact and generalizability of this finding as well as the significance of vitamin D supplementation in African descent patients therefore warrants further investigation.
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