Era Of Combination Antiretroviral Therapy Research Articles

Non-Hodgkin lymphoma in people living with human immunodeficiency syndrome

Introduction. Even in the era of combined antiretroviral therapy, the mortality rate in patients with human immunodeficiency virus infection remains high, especially with a contributing diagnosis of a malignant disease, such as non-Hodgkin lymphoma. Given the previous, the goal of this research was to establish the incidence of non-Hodgkin lymphoma in human immunodeficiency virus positive patients, as well as to determine their clinical characteristics and mortality in regard to patients with human immunodeficiency virus only. Material and Methods. The retrospective study included 396 human immunodeficiency virus-positive patients. Medical records were reviewed to analyze the average age, duration of infection, average duration of therapy, nCD4+ T-cell count, human immunodeficiency virus viral load, as well as the number and types of malignant diseases. Results. The average age of the patients was 44.2 years; the average nCD4+ T-cell count was 296.94 cells/?L, while the mortality rate was 14.65%. The leading causes of death were non-Hodgkin lymphoma and acquired immunodeficiency syndrome. The most frequently diagnosed malignancy was non-Hodgkin lymphoma, where the average count of nCD4+ T-cells was 162.29 cells/?L. Patients with human immunodeficiency virus and non-Hodgkin lymphoma had significantly lower nCD4+ T-cell count, in regard to patients with human immunodeficiency virus only, and the mortality rate in this group of patients was 85%. Conclusion. The incidence of non-Hodgkin lymphoma in human immunodeficiency virus-positive patients represents a growing threat, given the exceptionally high mortality. The nCD4+ T-cell count may indicate acquired immunodeficiency syndrome and late diagnosis of human immunodeficiency virus together are predictors for non-Hodgkin lymphoma and its poor outcome. It points to the importance of increasing the scope of human immunodeficiency virus testing, as well as finding a better treatment approach.

Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging

HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.

Severer nodular lesion in white matter than in gray matter in simian immunodeficiency virus-infected monkey, but not closely correlated with viral infection.

Immune cell accumulation and white matter anomaly are common features of HIV (human immunodeficiency virus) -infected patients in combination antiretroviral therapy (cART) era. Neuroimaging tests on cART treated patients displayed prominent diffuse white matter lesions. Notably, immune cell nodular lesion (NL) was a conspicuous type of pathological change in HIV/SIV (simian immunodeficiency virus) infected brain before cART. Therefore, we used SIV infected brain to investigate the distribution of those NLs in gray and white matters. We found a significant higher number of NLs in white matter than that in gray matter. However, virus infection correlated with macrophage NLs but not with microglia NLs, especially in white matter. In addition, NLs interrupted white matter integrity more severely, since even tiny nodules could disconnect nerve fibers in white matter tracts. In the gray matter with dense myelinated axons, NLs obviously encroached those fibers; in the area of few myelinated axons, small nodules well co-localized with extracellular matrix between neurons.

Metabolic Syndrome and Cardiovascular Disease Impacts on the Pathophysiology and Phenotype of HIV-Associated Neurocognitive Disorders.

Evidence from epidemiological studies on the general population suggests that midlife cardiovascular disease (CVD) and/or metabolic syndrome (MetS) are associated with an increased risk of cognitive impairment and dementia later in life. In the modern combined antiretroviral therapy (cART) era, as in the general population, CVD and MetS were strongly and independently associated with poorer cognitive performances of sustained immunovirologically controlled persons living with human immunodeficiency viruses (PLHIVs). Those findings suggest that CV/metabolic comorbidities could be implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND) and might be more important than factors related to HIV infection or its treatment, markers of immunocompetence, or virus replication. The association between CVD/MetS and cognition decline is driven by still not well-understood mechanisms, but risk might well be the consequence of increased brain inflammation and vascular changes, notably cerebral small-vessel disease. In this review, we highlight the correspondences observed between the findings concerning CVD and MetS in the general population and virus-suppressed cART-treated PLHIVs to evaluate the real brain-aging processes. Indeed, incomplete HIV control mainly reflects HIV-induced brain damage described during the first decades of the pandemic. Given the growing support that CVD and MetS are associated with HAND, it is crucial to improve early detection and assure appropriate management of these conditions.

Cytomegalovirus infection in HIV-infected patients in the era of combination antiretroviral therapy

BackgroundCytomegalovirus infection dramatically decreased with the introduction of antiretroviral therapy. Whether incidence, clinical characteristics and prognosis of cytomegalovirus in HIV infected patients, has changed over time is. scarcely known.MethodsRetrospective single-center study. Patients included in this study were all HIV infected patients that went to our center for any disease, and were diagnosed with cytomegalovirus, during the period 2004–2015. epidemiological, clinical and laboratory patients variables were collected in a clinical database. Clinical characteristics, incidence of cytomegalovirus and predictors of mortality during the study were assessed. Results were considered statistically significant when p < 0.05. All statistical analyses were calculated by SPSS version 20.0 (Chicago, IL,USA).ResultsFifty-six cases of cytomegalovirus infection, in HIV infected patients were identified during the study period (incidence rate-1.7 cases per 1000 persons/year). The most frequent presentation was systemic illness in 43% of cases. Of note,no patients presented with ophthalmic manifestations. The 30-days mortality was 18%. Predictors of mortality were, in the univariate analysis, admission to the intensive care unit OR 32.4 (3.65–287.06) p = 0.0001, and mechanic ventilation 84 OR (8.27–853.12) p = 0.0001, and ART OR 4.1 (0.97–17.31) p = 0.044. These variables were assessed by multivariate analysis, and only mechanical ventilation was statistically significant (p < 0.05)ConclusionIncidence of cytomegalovirus infection was higher than described in the antiretroviral therapy era. Clinical presentation has changed. Mechanic ventilation predicted mortality.

A clinical rule for the prediction of meningitis in HIV patients in the era of combination antiretroviral therapy.

The diagnosis of meningitis in HIV patients is challenging due to altered immune responses. Diagnostic scoring systems were recently proposed for use in research settings to help prompt and easy differential diagnosis. The objective of this study was to create a clinical prediction rule (CPR) for meningitis in HIV-infected patients and to address the enigma of differentiating bacterial (BM), TB (TBM) and cryptococcal (CCM) meningitis based on clinical features alone, which may be enhanced by easy-to-obtain laboratory testing. We retrospectively enrolled 352 HIV patients presenting with neurological manifestations suggesting meningitis over the last 18 y (2000-2018). Relevant clinical and laboratory information were retrieved from inpatient records. The features independently predicting meningitis or its different types in microbiologically proven meningitis cases were modelled by multivariate logistic regression to create a CPR in an exploratory data set. The performance of the meningitis diagnostic score was assessed and validated in a subset of retrospective data. AIDS clinical stage, injecting drug use, jaundice and cryptococcal antigen seropositivity were equally important as classic meningitic symptoms in predicting meningitis. Arthralgia and elevated cerebrospinal fluid Lactate dehydrogenase (LDH) were strong predictors of BM. Patients with cryptococcal antigenemia had 25 times the probability of having CCM, whereas neurological deficits were highly suggestive of TBM. The proposed CPRs have good diagnostic potential and would support decision-making in resource-poor settings.

Birth Prevalence of Congenital Cytomegalovirus Infection in HIV-Exposed Uninfected Children in the Era of Combination Antiretroviral Therapy

To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200cells/μL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

Antiretroviral-Mediated Microglial Activation Involves Dysregulated Autophagy and Lysosomal Dysfunction.

In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimuli, including viral products and cART. The current study was undertaken to understand the molecular mechanism(s) underlying cART-mediated activation of microglia. Herein we chose a combination of three commonly used drugs, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG). We demonstrated that exposure of microglia to this cART cocktail induced lysosomal membrane permeabilization (LMP), which subsequently resulted in impaired lysosomal functioning involving elevated pH and decreased cathepsin D (CTSD) activity. cART exposure of microglia resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the lysosomes with the autophagosome. Taken together, our findings suggest a novel mechanism by which cART impairs lysosomal functioning, resulting in dysregulated autophagy and increased neuroinflammation. Interventions aimed at lysosome protection could likely be envisioned as promising therapeutic targets for abrogating cART-mediated microglia activation, which in turn, could thus be considered as adjunctive therapeutics for the treatment of HAND pathogenesis.

National Temporal Trend Analysis of Infective Endocarditis among Patients Infected with HIV in Spain (1997-2014): A Retrospective Study.

Background: People living with human immunodeficiency virus (HIV) (PLWH) form a vulnerable population for the onset of infective endocarditis (IE). We aimed to analyze the epidemiological trend of IE, as well as its microbiological characteristics, in PLWH during the combined antiretroviral therapy era in Spain. Methods: We performed a retrospective study (1997–2014) in PLWH with data obtained from the Spanish Minimum Basic Data Set. We selected 1800 hospital admissions with an IE diagnosis, which corresponded to 1439 patients. Results: We found significant downward trends in the periods 1997–1999 and 2008–2014 in the rate of hospital admissions with an IE diagnosis (from 21.8 to 3.8 events per 10,000 patients/year; p < 0.001), IE incidence (from 18.2 to 2.9 events per 10,000 patients/year; p < 0.001), and IE mortality (from 23.9 to 5.5 deaths per 100,000 patient-years; p < 0.001). The most frequent microorganisms involved were staphylococci (50%; 42.7% Staphylococcus aureus and 7.3% coagulase-negative staphylococci (CoNS)), followed by streptococci (9.3%), Gram-negative bacilli (8.3%), enterococci (3%), and fungus (1.4%). During the study period, we found a downward trend in the rates of CoNS (p < 0.001) and an upward trends in streptococci (p = 0.001), Gram-negative bacilli (p < 0.001), enterococci (p = 0.003), and fungus (p < 0.001) related to IE, mainly in 2008–2014. The rate of community-acquired IE showed a significant upward trend (p = 0.001), while the rate of health care-associated IE showed a significant downward trend (p < 0.001). Conclusions: The rates of hospital admissions, incidence, and mortality related to IE diagnosis in PLWH in Spain decreased from 1997 to 2014, while other changes in clinical characteristics, mode of acquisition, and pathogens occurred over this time.

Inhibitory Control Deficits Associated with Upregulation of CB1R in the HIV-1 Tat Transgenic Mouse Model of Hand

In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indirectly via its actions on glia. The Go/No-Go (GNG) task was used to examine HAND in the Tat transgenic mouse model. The GNG task involves subjects discriminating between two stimuli sets in order to determine whether or not to inhibit a previously trained response. Data reveal inhibitory control deficits in female Tat(+) mice (p = .048) and an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB1R expression (r = −.543, p = .045), with CB1R expression predicting 30% of the variance of inhibitory control (R2 = .295, p = .045). Furthermore, there was a significant increase in spontaneous excitatory postsynaptic current (sEPSC) frequencies in Tat(+) compared to Tat(−) mice (p = .008, across sexes). The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001). Overall, the GNG task is a viable measure to assess inhibitory control deficits in Tat transgenic mice and results suggest a potential therapeutic treatment for the observed deficits with drugs which modulate endocannabinoid enzyme activity.Graphical Results of the Go/No-Go operant conditioning task reveal inhibitory control deficits in female transgenic Tat(+) mice without significantly affecting males. The demonstrated inhibitory control deficits appear to be associated with an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group.

Elevated indoleamine-2,3-dioxygenase enzyme activity in a novel mouse model of HIV-associated atherosclerosis.

HIV atherosclerosis and cardiovascular disease (CVD) represent a significant human health burden in the era of combination antiretroviral therapy (cART). The pathogenesis of HIV atherosclerosis is still poorly understood, due, in part, to the lack of a suitable small animal model. Indoleamine-2,3-dioxygenase (IDO) enzyme activity is the first and rate-limiting step in tryptophan catabolism and is measured by the kynurenine to tryptophan ratio (KTR). The serum KTR is a biomarker of inflammation and has recently been implicated as an important risk factor for CVD in patients living with HIV (PLWH) who are virologically suppressed under cART. However, IDO activity in HIV-associated CVD has not been studied in mouse model before. A novel mouse model of HIV atherosclerosis (Tg26/ApoE) was generated and examined for IDO activity and atherogenesis throughout 8 weeks on a high-fat diet. Tg26/ApoE mice were compared with Tg26 and ApoE single transgenic mice, before and during a high-fat diet. Serum kynurenine, tryptophan and percentage of aortic plaque formation were measured. Additionally, levels of relevant cytokines were investigated in Tg26/ApoE and ApoE. Tg26/ApoE developed an accelerated atherosclerosis with increasing levels of KTR that were associated with plaque progression. This accelerated plaque was potentially driven by elevated levels of circulating IL-6. These results indicate that Tg26/ApoE serve as a new mouse model for HIV-induced atherogenesis, and aid in understanding the role of tryptophan catabolism in the pathogenesis of HIV atherosclerosis/CVD.

What determines do-not-resuscitate status in critically ill HIV-infected patients admitted to ICU?

PurposeTo identify factors associated with do-not-resuscitate (DNR) status in critically ill patients infected with human immunodeficiency virus (HIV) admitted to the Intensive Care Unit (ICU) in the era of combination antiretroviral therapy (cART). Materials and methodsRetrospective cohort study of first-time admissions of HIV-infected patients to ICUs in Edmonton, Alberta, from 2002 to 2014. Multivariable logistic regression analysis was performed to identify factors associated with DNR status. ResultsThere were 282 HIV-infected patients with first-time ICU admissions, with an incidence rate of 6.6 per 1000 ICU admissions. Sixty-seven (24%) patients had a DNR designation and support was withdrawn in 37 (13%). In multivariable analysis, APACHE II score (OR 1.13; 95% CI, 1.08–1.19, p < 0.001), coronary artery disease (OR 5.70; 95% CI, 1.18–27.76, p = 0.031), prior opportunistic infection (OR 2.59; 95% CI, 1.20–5.57, p = 0.015) and duration of HIV infection (OR 1.07 per year; 95% CI, 1.01–1.14, p = 0.025) were independently associated with DNR status. Ethnicity, HIV risk factors, CD4 count and viral load were not associated with DNR status. ConclusionsOne in four patients had a DNR designation. Illness acuity, selected comorbidity, previous opportunistic infection and HIV duration were associated with DNR designation.

The current state of human immunodeficiency virus-associated lymphoma in Japan: a nationwide retrospective study of the Japanese Society of Hematology Blood Disease Registry.

This retrospective nationwide study sought to clarify the current status of human immunodeficiency virus (HIV)-associated lymphoma in Japan, where the number of new HIV infections remains high. We extracted data of patients with HIV-associated lymphoma who were registered in the database of the Japanese Society of Hematology Blood Disease Registry from January 2012 to December 2015, and analyzed patient characteristics, pathological diagnosis, and outcomes. The study cohort included 79 patients, including 75 male patients, with a median age of 52.5 (25-88) years. Among the lymphoma subtypes reported, the most common was diffuse large B cell lymphoma (DLBCL), followed by Burkitt lymphoma and primary central nervous system lymphoma. Estimated 3-year overall survival (OS) of all types of HIV-associated lymphoma was 68.8% [95% CI 68.2-69.4%]. However, the rate of extranodal involvement at the time of diagnosis was 49.2% and half of DLBCL was international prognostic index high or high-intermediate, with poor prognosis. Patients with primary effusion lymphoma died within 6months. Even in an era of combination antiretroviral therapy, HIV-associated lymphoma remains an important problem. Clinical manifestations identified in this study were aggressive, and outcomes remained poor, warranting continuous surveillance of HIV-associated lymphoma.

Metabolic Syndrome and Neurocognitive Deficits in HIV Infection.

The adverse consequences of HIV and related comorbidities on the central nervous system remain prevalent in the era of combination antiretroviral therapy. Metabolic syndrome (MetS) is a common comorbidity in HIV and has been linked to increased neurocognitive impairment in the general population. We investigated the association between MetS and neurocognition among persons living with HIV (PLHIV). Participants included 109 PLHIV and 92 HIV-uninfected adults (HIV-) from the Multi-dimensional Successful Aging cohort study at the University of California San Diego (age: M = 50.8, SD = 8.0). Participants completed neuromedical, psychiatric, and neurocognitive assessments. Based on a comprehensive neurocognitive battery, we examined global neurocognitive deficits (based on the entire battery) and neurocognitive deficits in 7 domains (verbal fluency, learning, recall, executive function, working memory, speed of information processing, and fine motor skills). MetS was determined via the standard criteria by the National Cholesterol Education Program's Adult Treatment Panel-III. Covariates examined included demographics and psychiatric comorbidities (and HIV disease characteristics among PLHIV). MetS had an independent significant effect on global neurocognitive deficits among PLHIV (P = 0.03) but not among their HIV- counterparts (P = 0.93). Among PLHIV, MetS was most strongly associated with the neurocognitive domains of learning, fine motor skills, and executive function. Diabetes and elevated triglycerides were the MetS components most strongly linked with increased global neurocognitive deficits in PLHIV. The present findings underscore the need for early identification of PLHIV at risk for MetS and the implementation of preventive and treatment approaches to lessen the development of MetS and neurocognitive impairment among PLHIV.

Epidemiological trend of hospitalized acute and recurrent hepatitis C in Spain

Introduction: Acute hepatitis C virus (HCV) infection (AHC) is often difficult to identify due to the lack of symptoms (around 85% of cases) [1,2]. Despite the decline of HCV transmission via blood-to-blood due to donor screening programs and a decline in intravenous drug use (IDUs) [3], the incidence of sexual transmission has now increased, particularly in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), arousing great interest in this new public health problem [4,5]. This is the first study to evaluate the incidence of hospital admissions and mortality related to admitted AHC and AHC recurrences, with particular attention to HIV-infected patients, as well as to analyze its trend through the combination antiretroviral therapy (cART) era (1997–2012) in Spain. Materials and methods: We performed a retrospective study on patients with an AHC diagnosis in the Spanish Minimum Basic Data Set (MBDS). Patients were classified as HCV-monoinfected patients and HIV/HCV-coinfected patients. The outcome variables were: i) AHC-related hospital admission; ii) AHC-related mortality (intra-hospital mortality); iii) hospital admissions related to AHC recurrences. The data were treated with full confidentiality, according to Spanish legislation. MBDS is regulated by an organic law that sets out how institutions must proceed with health-related personal data. Informed consent is not required because personal data are collected for the exercise of the functions proper to public administrative bodies. The Spanish Ministry of Health confirmed that our study fulfilled all the appropriate ethical considerations, according to Spanish legislation. Results: Overall, 5792 patients were diagnosed with AHC during the study period, 4831 subjects were HCV-monoinfected, 961 individuals were HIV/HCV-coinfected and there were 115 (1.99%) recurrences, of them, 97 (2.00%) were HVC monoinfected and 18 (1,88%) HIV/HCV coinfected, showing similar incidence in both groups. The incidence of AHC-related hospital admission in HIV/HCV-coinfected patients was 0.81 per 10,000 person-years (p-y) while in HCV-monoinfected, it was 1.2 per 100,000 p-y (p < 0.001). Both groups showed a dramatic decrease in hospital admissions during the study period (p < 0.001). The mortality over the whole follow-up in the HIV/HCV-coinfected group was 2.2 per 10,000 p-y, while in the HCV-monoinfected group it was 2.0 per 100,000 p-y (p < 0.001). AHC-related mortality diminished significantly in both groups (approximately 2–3 times) during the study period (p < 0.001). The adjusted likelihood of death for AHC was 1.90 (95%CI =2.07–3.02) times higher in HIV/HCV-coinfected patients than in HCV-monoinfected. The adjusted likelihood of AHC recurrence during the follow-up was 1.31 times higher in HIV/HCV-coinfected patients than in HCV-monoinfected patients [adjusted hazard ratio (aHR) = 1.31 (95%CI = 1.05–1.63); p = 0.013]. Discussion and conclusions: HIV/HCV-coinfected individuals were at higher risk of hospital admissions and deaths related to AHC during the cART era, with higher incidence and mortality than HCV-monoinfected subjects. Recurrence of AHC-related to hospital admissions was observed.

Different roles of frontal versus striatal atrophy in HIV-associated neurocognitive disorders.

Gray matter (GM) atrophy is frequently detected in persons living with HIV, even in the era of combination antiretroviral therapy (cART), but the specificity of regions affected remains elusive. For instance, which regions are consistently affected in HIV? In addition, atrophy at which regions is frequently associated with neurocognitive impairment in HIV? Resolving these questions can potentially help to establish the possible neural profiles of HIV-associated neurocognitive disorders (HAND) severity, which currently is solely defined by neurobehavioral assessments. Here, we addressed these questions using a novel meta-analysis technique, the colocalization-likelihood estimation (CLE) technique, to quantitatively synthesize the findings of GM atrophy in HIV+ adults. Twenty-one of 386 studies published between 1988 and November 2017 and identified in PubMed were selected, plus four identified in other resources. In the end, 25 studies (1,370 HIV+ adults, 889 HIV- controls) were included in the meta-analysis. This technique revealed that GM atrophy in HIV+ adults was dominated by two distinct but nonexclusive profiles: frontal (including anterior cingulate cortex, [ACC]) atrophy, which was associated withHIV-disease and consistently differentiated HIV+ adults from HIV- controls; and caudate/striatum atrophy, which was associated with neurocognitive impairment. The critical role of caudate/striatum atrophy in neurocognitive impairment was further supported by a separate data analysis, which examined the findings of correlation analyses between GM and neurocognitive performance. These results suggest that the frontal lobe and the striatum play critical but differential roles in HAND. A neural model of HAND severity was proposed with several testable predictions.

Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer's disease?

HIV infection in the combination antiretroviral therapy (cART) era has become a chronic disease with a life expectancy almost identical to those free from this infection. Concomitantly, chronic diseases such as neurodegenerative diseases have emerged as serious clinical problems. HIV-induced cognitive changes, although clinically very diverse are collectively called HIV-associated neurocognitive disorder (HAND). HAND, which until the introduction of cART manifested clinically as a subcortical disorder, is now considered primarily cognitive disorder, which makes it similar to diseases like Alzheimer's (AD) and Parkinson's disease (PD). The pathogenesis involves either the direct effects of the virus or the effect of viral proteins such as Tat, Ggp120, and Nef. These proteins are either capable of destroying neurons directly by inducing neurotoxic mediators or by initiating neuroinflammation by microglia and astrocytes. Recently, it has become recognized that HIV infection is associated with increased production of the beta-amyloid peptide (Aβ) which is a characteristic of AD. Moreover, amyloid plaques have also been demonstrated in the brains of patients suffering from HAND. Thus, the question arises whether this production of Aβ indicates that HAND may lead to AD or it is a form of AD or this increase in Aβ production is only a bystander effect. It has also been discovered that APP in HIV and its metabolic product Aβ in AD manifest antiviral innate immune peptide characteristics. This review attempts to bring together studies linking amyloid precursor protein (APP) and Aβ production in HIV infection and their possible impact on the course of HAND and AD. These data indicate that human defense mechanisms in HAND and AD are trying to contain microorganisms by antimicrobial peptides, however by employing different means. Future studies will, no doubt, uncover the relationship between HAND and AD and, hopefully, reveal novel treatment possibilities.

Epstein-Barr virus biomarkers have no prognostic value in HIV-related Hodgkin lymphoma in the modern combined antiretroviral therapy era.

Epstein-Barr virus (EBV) has been implicated in lymphomagenesis of HIV-related classical Hodgkin lymphoma (HIV-cHL). The utility of EBV molecular and serological biomarkers has scarcely been examined in HIV-cHL in the recent combined antiretroviral therapy (cART) era. We evaluated EBV DNA load and a panel of EBV antibodies in HIV-cHL patients prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015. Pretreatment whole blood, plasma EBV DNA load and serological profiles were analysed in 63 HIV-infected patients diagnosed with cHL. For the 42 patients with available material, comparisons were performed between values at diagnosis and 6 months after the initiation of chemotherapy. Pretreatment whole blood and plasma EBV DNA loads were positive in 84 and 59% of HIV-cHL patients, respectively. Two-year progression-free survival estimates did not differ between the patients with pretreatment whole blood (n = 53) or plasma (n = 37) EBV DNA(+) and the patients with pretreatment whole blood (n = 10) or plasma (n = 26) EBV DNA(-) (92 vs. 80% or 89 vs. 92%, P = 0.36 and 0.47, respectively). At diagnosis, 47% of patients harboured an EBV reactivation serological profile. Following chemotherapy, whole blood and plasma EBV DNA levels significantly declined from medians of 1570 [interquartile range, 230-3760) and 73 (0-320) copies/ml to 690 (0-1830) and 0 (0-0) copies/ml, respectively (P = 0.02 and P < 0.0001, respectively]. Anti-EBV IgG antibody level significantly dropped at 6-month follow-up (P = 0.004). Whole blood and plasma EBV DNA loads do not constitute prognostic markers in HIV-cHL patients in the modern cART era.

The effects of free condom distribution on HIV and other sexually transmitted infections in men who have sex with men

BackgroundHIV and other sexually transmitted infections remain a burden on men who have sex with men in the era of effective combination antiretroviral therapy. New prevention efforts are therefore needed. One of these approaches is the current country-wide free condom distribution at gay bars with darkrooms and gay saunas in the Netherlands. This study assessed the effects of free condom distribution on incidence and burden of disease of HIV and other sexually transmitted infections.MethodsA static model was constructed to calculate the impact of free condom distribution on HIV, hepatitis C, chlamydia, gonorrhoea, and syphilis among men who have sex with men visiting these venues. Outcomes included new infections averted and disability-adjusted life years averted. Scenario studies were performed to predict the effects of a further increase of condom use, condom effectiveness and coverage. Lastly, cost-effectiveness and sensitivity analyses were performed.ResultsOur model showed that condom use at public sex venues increased after the intervention. Annual incidence risk decreased, ranging from 5.73% for gonorrhoea to 7.62% for HIV. The annual number of new infections averted was largest for chlamydia and gonorrhoea (261 and 394 infections, respectively), but 42 new HIV infections were averted as well. In scenarios where condom use and condom effectiveness were further increased, the number of infections reduced more extensively. Over 99% of the decrease in burden of disease was due to HIV. The intervention was cost-effective and cost-saving (for every €1 spent on condom distribution, €5.51 was saved) and remained this in all sensitivity analyses.ConclusionsFree condoms at public sex venues could reduce the transmission of HIV and other sexually transmitted infections. Condom distribution is an affordable and easily implemented intervention that could reduce the burden of disease in men who have sex with men substantially.

HIV-Nef Protein Persists in the Lungs of Aviremic Patients with HIV and Induces Endothelial Cell Death.

It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte-activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV+ patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial-cadherin+ endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.