Value of Perfusion-Weighted MR Imaging in the Assessment of Early Cerebral Alterations in Neurologically Asymptomatic HIV-1-Positive and HCV-Positive Patients

Background and Purpose

Asymptomatic central nervous system (CNS) involvement occurs in the early stage of the human immunodeficiency virus (HIV) infection. It has been documented that the hepatitis C virus (HCV) can replicate in the CNS. The aim of the study was to evaluate early disturbances in cerebral microcirculation using magnetic resonance (MR) perfusion-weighted imaging (PWI) in asymptomatic HIV-1-positive and HCV-positive patients, as well as to assess the correlation between PWI measurements and the clinical data.

Materials and Methods

Fifty-six patients: 17 HIV-1-positive non-treated, 18 HIV-1-positive treated with combination antiretroviral therapy (cART), 7 HIV-1/HCV-positive non-treated, 14 HCV-positive before antiviral therapy and 18 control subjects were enrolled in the study. PWI was performed with a 1.5T MR unit using dynamic susceptibility contrast (DSC) method. Cerebral blood volume (CBV) measurements relative to cerebellum (rCBV) were evaluated in the posterior cingulated region (PCG), basal ganglia (BG), temporoparietal (TPC) and frontal cortices (FC), as well as in white matter of frontoparietal areas. Correlations of rCBV values with immunologic data and liver histology activity index (HAI) were analyzed.

Results

Significantly lower rCBV values were found in the right TPC and left FC as well as in PCG in HIV-1-positive naïve (p = 0.009; p = 0.020; p = 0.012), HIV-1 cART treated (p = 0.007; p = 0.009; p = 0.033), HIV-1/HCV-positive (p = 0.007; p = 0.027; p = 0.045) and HCV-positive patients (p = 0.010; p = 0.005; p = 0.045) compared to controls. HIV-1-positive cART treated and HIV-1/HCV-positive patients demonstrated lower rCBV values in the right FC (p = 0.009; p = 0.032, respectively) and the left TPC (p = 0.036; p = 0.005, respectively), while HCV-positive subjects revealed lower rCBV values in the left TPC region (p = 0.003). We found significantly elevated rCBV values in BG in HCV-positive patients (p = 0.0002; p<0.0001) compared to controls as well as to all HIV-1-positive subjects. There were no significant correlations of rCBV values and CD4 T cell count or HAI score.

Conclusions

PWI examination enables the assessment of HIV-related as well as HCV-related early cerebral dysfunction in asymptomatic subjects. HCV-infected patients seem to reveal the most pronounced perfusion changes.     

Prevalence of Alzheimer’s Pathologic Endophenotypes in Asymptomatic and Mildly Impaired First-Degree Relatives

Objective

A positive family history (FH) is a risk factor for late-onset Alzheimer’s disease (AD). Our aim was to examine the effects of FH on pathological and neuronal loss biomarkers across the cognitive spectrum.

Design

Cross-sectional analyses of data from a national biomarker study.

Setting

The Alzheimer’s Disease Neuroimaging Initiative national study.

Patients

257 subjects (ages 55–89), divided into cognitively normal (CN), mild cognitive impairment (MCI), and AD groups, with CSF and FH data.

Outcome Measures

Cerebrospinal fluid (CSF) Aβ42, tau, and tau/Aβ42 ratio, MRI-measured hippocampal volumes.

Statistics

Univariate and multivariate analyses.

Results

In MCI, CSF Aβ42 was lower (p = .005), t-tau was higher (p = 0.02) and t-tau/Aβ42 ratio was higher (p = 0.002) in FH+ than FH− subjects. A significant residual effect of FH on pathologic markers in MCI remained after adjusting for ApoE4 (p<0.05). Among CN, 47% of FH+ exhibited “pathologic signature of AD” (CSF t-tau/Aβ42 ratio >0.39) versus 21% of FH− controls (p = 0.03). The FH effect was not significant in AD subjects. Hippocampal and intracranial volumes did not differ between FH+ and FH− subjects in any group.

Conclusions

A positive family history of late-onset AD is associated with a higher prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in MCI. The unexplained genetic heritability in family history is about the half the size of the ApoE4 effect. Longitudinal studies are warranted to more definitively examine this issue.     

Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa

Background

In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.

Methodology/Principle Findings

We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm³ (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing.

Conclusions/Significance

We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.     

Sleep Extension Improves Neurocognitive Functions in Chronically Sleep-Deprived Obese Individuals

Background

Sleep deprivation and obesity, are associated with neurocognitive impairments. Effects of sleep deprivation and obesity on cognition are unknown, and the cognitive long-term effects of improvement of sleep have not been prospectively assessed in short sleeping, obese individuals.

Objective

To characterize neurocognitive functions and assess its reversibility.

Design

Prospective cohort study.

Setting

Tertiary Referral Research Clinical Center.

Patients

A cohort of 121 short-sleeping (<6.5 h/night) obese (BMI 30–55 kg/m²) men and pre-menopausal women.

Intervention

Sleep extension (468±88 days) with life-style modifications.

Measurements

Neurocognitive functions, sleep quality and sleep duration.

Results

At baseline, 44% of the individuals had an impaired global deficit score (t-score 0–39). Impaired global deficit score was associated with worse subjective sleep quality (p = 0.02), and lower urinary dopamine levels (p = 0.001). Memory was impaired in 33%; attention in 35%; motor skills in 42%; and executive function in 51% of individuals. At the final evaluation (N = 74), subjective sleep quality improved by 24% (p<0.001), self-reported sleep duration increased by 11% by questionnaires (p<0.001) and by 4% by diaries (p = 0.04), and daytime sleepiness tended to improve (p = 0.10). Global cognitive function and attention improved by 7% and 10%, respectively (both p = 0.001), and memory and executive functions tended to improve (p = 0.07 and p = 0.06). Serum cortisol increased by 17% (p = 0.02). In a multivariate mixed model, subjective sleep quality and sleep efficiency, urinary free cortisol and dopamine and plasma total ghrelin accounted for 1/5 of the variability in global cognitive function.

Limitations

Drop-out rate.

Conclusions

Chronically sleep-deprived obese individuals exhibit substantial neurocognitive deficits that are partially reversible upon improvement of sleep in a non-pharmacological way. These findings have clinical implications for large segments of the US population.

Trail registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898. NIDDK protocol 06-DK-0036     

Plasmodium falciparum Infection Significantly Impairs Placental Cytokine Profile in HIV Infected Cameroonian Women

Background

Placental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women.

Materials and Methods

P. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses.

Results

Placental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5–4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3–1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-α mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-α/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-α was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery.

Conclusions

These results show that P. falciparum infection profoundly modifies the placenta cytokine environment and acts as a confounding factor, masking the impact of HIV-1 in co-infected women. This interplay between the two infections might have implications in the in utero MTCT of HIV-1 in areas where HIV-1 and P. falciparum co-circulate.     

Comparable Long-Term Efficacy of Lopinavir/Ritonavir and Similar Drug-Resistance Profiles in Different HIV-1 Subtypes

Background

Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment.

Methods

Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS.

Results

607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16).

Conclusions

Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment.     

Traditional but Not HIV-Related Factors Are Associated with Nonalcoholic Fatty Liver Disease in Asian Patients with HIV-1 Infection

Background

The prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) are largely unknown in HIV-1 monoinfected patients.

Methods

The present study elucidated the prevalence and factors associated with NAFLD among Asian patients with HIV-1 infection who underwent abdominal ultrasonography between January 2004 and March 2013. Diagnosis of NAFLD was based on the liver to kidney contrast and diffusion in hepatic echogenicity. Uni- and multi-variate logistic regression analyses were applied to estimate factors associated with NAFLD.

Results

435 Asian patients free of chronic hepatitis B or C virus infection and without excessive alcohol intake were analyzed. NAFLD was diagnosed in 135 (31%) patients. Obesity (BMI >30 kg/m²) was evident in 18 (4.1%) patients, and BMI was >25 kg/m² in 103 (24%). Multivariate analysis identified higher BMI (per 1 kg/m² increment, adjusted OR = 1.198; 95% CI, 1.112–1.290; p<0.001), dyslipidemia (adjusted OR = 2.045; 95% CI, 1.183–3.538; p = 0.010), and higher ALT to AST ratio (per 1 increment, adjusted OR = 3.557; 95% CI, 2.129–5.941; p<0.001) as significant factors associated with NAFLD. No HIV-specific variables, including treatment with dideoxynucleoside analogues (didanosine, stavudine, and zalcitabine) and cumulative duration of antiretroviral therapy (ART), were associated with NAFLD.

Conclusions

The incidence of NALFD among Asian patients with HIV-1 infection is similar to that in Western countries. NAFLD was associated with high BMI, dyslipidemia, and high ALT/AST ratio, but not with HIV-related factors. The results highlight the importance of early recognition and management of NAFLD and traditional factors associated with NAFLD for Asian patients with HIV-1 infection.     

Helminth-Associated Systemic Immune Activation and HIV Co-receptor Expression: Response to Albendazole/Praziquantel Treatment

Background

It has been hypothesized that helminth infections increase HIV susceptibility by enhancing systemic immune activation and hence contribute to elevated HIV-1 transmission in sub-Saharan Africa.

Objective

To study systemic immune activation and HIV-1 co-receptor expression in relation to different helminth infections and in response to helminth treatment.

Methods

HIV-negative adults with (n = 189) or without (n = 57) different helminth infections, as diagnosed by Kato-Katz, were enrolled in Mbeya, Tanzania. Blinded to helminth infection status, T cell differentiation (CD45RO, CD27), activation (HLA-DR, CD38) and CCR5 expression was determined at baseline and 3 months after Albendazole/Praziquantel treatment. Plasma cytokine levels were compared using a cytometric bead array.

Results

Trichuris and Ascaris infections were linked to increased frequencies of “activated” CD4 and/or CD8 T cells (p<0.05), whereas Hookworm infection was associated with a trend towards decreased HLA-DR⁺ CD8 T cell frequencies (p = 0.222). In Trichuris infected subjects, there was a linear correlation between HLA-DR⁺ CD4 T cell frequencies and the cytokines IL-1β and IL-10 (p<0.05). Helminth treatment with Albendazole and Praziquantel significantly decreased eosinophilia for S. mansoni and Hookworm infections (p<0.005) but not for Trichuris infection and only moderately modulated T cell activation. CCR5 surface density on memory CD4 T cells was increased by 1.2-fold during Trichuris infection (p-value: 0.053) and reduced after treatment (p = 0.003).

Conclusions

Increased expression of T cell activation markers was associated with Trichuris and Ascaris infections with relatively little effect of helminth treatment.     

High Prevalence of Illicit Drug Use in Men Who Have Sex with Men with HIV-1 Infection in Japan

Objective

To examine the prevalence of illicit drug use among men who have sex with men (MSM) with HIV-1 infection in Japan, where the life-time prevalence of illicit drug use in the general population is only 2.9%.

Design

A single-center cross-sectional study at a large HIV clinic in Tokyo, which treats approximately 15% of HIV-1 infected patients in Japan.

Methods

The prevalence of illicit drug use and the assciation of characteristics and social demographics of the patients with illicit drug use were examined. Patients who visited the clinic for the first time from 2005 to 2010 were enrolled. Relevant variables were collected using a structured interview and from the medical records. Multivariate logistic regression analyses were applied to estimate the odds of association of MSM over non-MSM HIV-infected patients with illicit drug use.

Results

1,196 patients were enrolled. They were mostly Japanese men of relatively young age. Illicit drug use (including injection drugs) was reported by 35% of the patients (by 40% of MSM), and 4% were IDU while 5% were on methamphetamine. 2% of the population was arrested due to illicit drugs. MSM was significantly associated with illicit drug use (adjusted OR = 4.60; 95% CI, 2.88–7.36; p<0.01). Subgroup analysis of the patients stratified by three age groups (≤30, 31 to 40, and >40) showed that the odds of association of MSM with illicit drug use was the strongest in the youngest age group (≤30 years: adjusted OR = 7.56; 95% CI, 2.86–20.0; p<0.01), followed by the oldest (>40 years: adjusted OR = 6.15; 95% CI, 2.40–15.8; p<0.01), and the weakest in the group aged 31 to 40 (adjusted OR = 3.39; 95% CI, 1.73–6.63; p<0.01).

Conclusions

The prevalence of illicit drug use is high among MSM patients with HIV-1 infection in Japan. Effective intervention for illicit drug use in this population is warranted.     

Postcoital Bioavailability and Antiviral Activity of 0.5% PRO 2000 Gel: Implications for Future Microbicide Clinical Trials

Background

The pharmacokinetics and pharmacodynamics of vaginal microbicides are typically assessed among sexually abstinent women. However, the physical act of sex may modulate gel distribution, and preclinical studies demonstrate seminal plasma interferes with the antiviral activity of several microbicides. This study compared the biological activity and concentration of PRO 2000 in cervicovaginal lavage (CVL) collected in the absence or following coitus.

Methods

CVL samples were collected from ten heterosexual couples at baseline, after sex, after a single dose of 0.5% PRO 2000 gel and sex, and after gel application without sex. The impact of CVL on HIV-1 infection of TZM-bl cells and HSV-2 infection of CaSki cells was monitored by luciferase and plaque assay, respectively. PRO 2000 concentrations were measured by fluorescence.

Results

CVL collected after PRO 2000 application significantly inhibited HIV-1 and HSV-2 (p = 0.01). However, the antiviral activity was reduced following sex and no significant protective effect was observed in postcoital CVL obtained in the presence compared to the absence of PRO 2000 for HIV (p = 0.45) or HSV-2 (p = 0.56). Less PRO 2000 was recovered in postcoital CVL, which, in conjunction with interference by seminal plasma, may have contributed to lower antiviral activity.

Conclusions

Postcoital responses to PRO 2000 differ from precoital measures and the results obtained may provide insights into the clinical trial findings in which there was no significant protection against HIV-1 or HSV-2. Postcoital studies should be incorporated into clinical studies before embarking on large-scale efficacy trials.     

Differences in Simulated Doctor and Patient Medical Decision Making: A Construal Level Perspective

Background

Patients are often confronted with diverse medical decisions. Often lacking relevant medical knowledge, patients fail to independently make medical decisions and instead generally rely on the advice of doctors.

Objective

This study investigated the characteristics of and differences in doctor–patient medical decision making on the basis of construal level theory.

Methods

A total of 420 undergraduates majoring in clinical medicine were randomly assigned to six groups. Their decisions to opt for radiotherapy and surgery were investigated, with the choices described in a positive/neutral/negative frame × decision making for self/others.

Results

Compared with participants giving medical advice to patients, participants deciding for themselves were more likely to select radiotherapy (F_{1, 404} = 13.92, p = 011). Participants from positive or neutral frames exhibited a higher tendency to choose surgery than did those from negative frames (F_{2, 404} = 22.53, p<.001). The effect of framing on independent decision making was nonsignificant (F_{2, 404} = 1.07, p = 35); however the effect of framing on the provision of advice to patients was significant (F_{2, 404} = 12.95, p<.001). The effect of construal level was significant in the positive frame (F_{1, 404} = 8.06, p = 005) and marginally significant in the neutral frame (F_{2, 404} = 3.31, p = 07) but nonsignificant in the negative frame (F_{2, 404} = .29, p = 59).

Conclusion

Both social distance and framing depiction significantly affected medical decision making and exhibited a significant interaction. Differences in medical decision making between doctors and patients need further investigation.     

Changes in Natural Killer Cell Activation and Function during Primary HIV-1 Infection

Background

Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.

Methodology/Principal Findings

Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α₄β₇). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32''p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR_pos) NK cells increased following HIV acquisition (p = 0.006), and KIR_pos NK cells were less activated than KIR_neg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).

Conclusions/Significance

Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.     

GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

Background

The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.

Methods

Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).

Results

Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.

Conclusions

Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.