Lower Nadir CD4 Research Articles

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study.

BackgroundDual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.MethodsWe retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.ResultsFour hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6–97.2) without M184V and 87.8% (95% CI, 78.4–97.2) with M184V (P = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51–199 copies/mL) was 79.8% (95% CI, 67.8%–91.8%) with M184V vs 90.1% (95% CI, 84.0%–96.2%) without M184V (P = .016).ConclusionsPrevious selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.

High-grade anal intraepithelial neoplasia is associated with HIV-1 RNA rectal shedding in virologically suppressed MSM

The protective effect of ART has not yet been definitively established in MSM. We aimed to characterize the factors associated with persistent HIV-1 RNA rectal shedding. Prospective study including virologically suppressed MSM from an HIV cohort. High-resolution anoscopy (HRA) was performed for screening of anal dysplasia, and rectal sampling for HIV-1 RNA quantification and sexually transmitted infections (STIs) investigation through multiplex PCR. Both generalized linear mixed (GLM) and zero-altered negative binomial (ZANB) models were performed. One hundred and fifty-five rectal swab samples from 132 virologically suppressed MSM were included. HIV-1 RNA was detectable in 61 (39.3%) samples, with median (IQR) rectal viral load (rVL) of 295.8 (158.8-522) copies/swab. Multivariable GLM showed that the presence of high-grade anal intraepithelial neoplasia (HG-AIN; OR 2.85 [95% CI 1.10-7.38]) and a protease inhibitor-based regimen (OR 2.49 [0.98-6.34]) resulted in increased risk for rectal HIV-1 shedding, whereas higher nadir CD4+/CD8+ T-cell ratio (OR 0.18 [0.04-0.93]) was negatively associated with rectal shedding. ZANB analyses showed that the best predictors of having detectable rVL were lower nadir CD4+/CD8+ T-cell ratio (OR 0.98 [0.96-0.99]) and PI-based regimens (OR 4.85 [1.29-18.24]); the presence of HG-AIN (RR 2.50 [1.41-4.45]), and a higher burden of STIs (RR 1.39 [1.03-1.85]) were predictors of rectal HIV-1 shedding intensity. The prevalence of HIV-1 RNA rectal shedding is high in virologically suppressed MSM. In addition to ART and the immune system integrity, local factors, including the co-existence of HG-AIN and the burden of STIs, may account for the persistence of HIV-1 RNA shedding in rectal mucosa.

Structural connectome differences in HIV infection: brain network segregation associated with nadir CD4 cell count.

This study investigated structural brain organization using diffusion tensor imaging (DTI) in 35 HIV-positive and 35 HIV-negative individuals. We used global and nodal graph theory metrics to investigate whether HIV was associated with differences in brain network organization based on fractional anisotropy (FA) and mean diffusivity (MD). Participants also completed a comprehensive neuropsychological testing battery. For global network metrics, HIV-positive individuals displayed a lower FA clustering coefficient relative to HIV-negative individuals. For nodal network metrics, HIV-positive individuals had less MD nodal degree in the left thalamus. Within HIV-positive individuals, the FA global clustering coefficient was positively correlated with nadir CD4 cell count. Across the sample, cognitive performance was negatively correlated with characteristic path length and positively correlated with global efficiency for FA. These results suggest that, despite management with combination antiretroviral therapy, HIV infection is associated with altered structural brain network segregation and thalamic centrality and that low nadir CD4 cell count may be a risk factor. These graph theory metrics may serve as neural biomarkers to identify individuals at risk for HIV-related neurological complications.

Resistance detected in PBMCs predicts virological rebound in HIV-1 suppressed patients switching treatment

BackgroundGenotypic resistance test (GRT) performed in peripheral blood mononuclear cells (PBMC) represents a chance to evaluate resistance in virologically suppressed HIV infected patients. ObjectivesTo evaluate the impact of baseline resistance detected through PBMC GRT on virological rebound after switching treatment. Study designBaseline genotypic susceptibility scores (GSS) from PBMC GRT (DNA-GSS) and from previous cumulative plasma GRTs (when available, pRNA-GSS) were evaluated. Survival analysis was used to assess the probability and predictors of virological rebound (VR). Results227 virologically suppressed patients were analysed. Twenty-four months after switching therapy, the probability of VR was 15.3%. Patients showing an intermediate or full resistant DNA-GSS had a higher probability of experiencing VR compared to those carrying a fully susceptible DNA-GSS (27.2% vs. 13.7%, p = 0.001). By multivariable Cox regression, patients with an intermediate/full resistant DNA-GSS, with a nadir CD4 count <100 cell/mm3 and with a shorter time of previous virological suppression showed a higher adjusted hazard of experiencing VR.In a sub-group of 114 patients with previous plasma GRTs available, patients with an intermediate or fully resistance showed by both GSSs (from plasma and PBMCs) had the highest probability of experiencing VR. ConclusionsResistance detected in proviral DNA, together with a low nadir CD4 count and a short previous virological control, predicts VR after therapy switching in virologically suppressed patients. PBMC GRT can be a useful tool for tailoring treatment switch, especially if paired with information about previous cumulative resistance and previous viro-immunological history.

HIV-1 non-R5 tropism correlates with a larger size of the cellular viral reservoir and a detectable residual viremia in patients under suppressive ART

BackgroundThe influence of HIV-1 co-receptor usage on the course of therapy in subjects fully responding to ART has been poorly investigated. ObjectivesTo explore the relationship between co-receptor tropism and cellular reservoir size, residual viremia and subsequent virological outcome in ART-treated patients with HIV-1 RNA stable <50 copies/mL. Study designViral co-receptor usage was predicted by viral env DNA sequencing with geno2pheno interpretation (FPR20%) and classified as R5 and non-R5. Total blood-associated HIV-1 DNA levels (log10 copies/106 leukocytes) were measured by qRT-PCR (5′LTR). Residual plasma viremia was categorized as detectable (1–49 cps/mL) or undetectable (<1 copy/mL). Virological rebounds (any HIV-1 RNA >50 copies/mL) were evaluated over 96 weeks. ResultsThe study included 116 subjects. Patients with R5 virus (n = 59) and non-R5 virus (n = 57) were homogeneous for the main characteristics except for the lower nadir CD4 cell count in the non-R5 group. Patients with non-R5 variants showed higher levels of HIV-1 DNA as compared to patients with R5 virus: mean 2.47 (95% CI 2.37–2.56) vs 2.17 (2.08–2.26) (p < 0.001). Moreover, a higher proportion of patients in the non-R5 group displayed detectable residual viremia with respect to the R5-group (54.4% vs 32.2%, p = .016). Detectable residual viremia was found to be significantly associated with viral rebounds. ConclusionThe presence of non-R5 viral DNA variants is related to a higher probability of residual viremia and to a larger size of the cellular viral reservoir in this setting. These data highlight a potential role of viral tropism in the monitoring of HIV-1 infection in virologically controlled subject.

Risk of skin cancer in patients with HIV: A Danish nationwide cohort study

The risk of skin cancer in patients with HIV has not been extensively studied. We sought to determine the risk of skin cancer in patients with HIV and compare it with the risk in the background population. In a matched, nationwide, population-based cohort study, we compared the risk of skin cancer in 4280 patients with HIV from the Danish HIV cohort study with a background population cohort, according to the level of immunosuppression and route of transmission. Primary outcomes were time to first basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or malignant melanoma. Patients with HIV had an increased risk of BCC and SCC with incident rate ratios of 1.79 (95% confidence interval 1.43-2.22) and 5.40 (95% confidence interval 3.07-9.52), respectively, compared with the background population. We observed no increased risk of malignant melanoma. Low nadir CD4 cell count was associated with an increased risk of SCC. The increased risk of BCC among patients with HIV was restricted to men who had sex with men. This study was observational and included a small number of patients with melanoma. Patients with HIV have an increased risk of BCC and SCC. Low nadir, but not current, CD4 cell count as a marker of immunosuppression was associated with an increased risk of SCC.

Abstract P189: Factors Associated With Stenosis on Invasive Coronary Angiography for Persons Living With Human Immunodeficiency Virus (PLWH): The HIV Electronic Comprehensive Cohort of CVD Complications (HIVE-4CVD)

Background: Persons living with HIV (PLWH) have greater risks for atherosclerotic cardiovascular disease (ASCVD) than uninfected persons. However, data are sparse regarding HIV-specific factors associated with coronary atherosclerosis. Methods: HIVE-4CVD is an electronic data repository of demographic and clinical data collected during the routine clinical care of 5041 PLWH and 10082 uninfected controls frequency matched on age, sex, race, zip code, and clinic location receiving care at Northwestern Medicine from 1/1/2000 to 5/17/2017. Using validated natural language extraction algorithms, we analyzed data on coronary stenosis severity for the 286 PLWH and 266 uninfected controls in HIVE-4CVD who underwent coronary angiography. Stenosis severity was recorded as the highest percentage of stenosis noted for each patient in each artery (LAD, LCx, RCA). Multivariable logistic regression models adjusted for demographics and CVD risk factors were used to evaluate odds of significant (≥50%) coronary stenosis (1) for PLWH versus uninfected controls and (2) across different levels of HIV viremia and immune suppression among PLWH. Results: Of the 286 PLWH and 266 uninfected controls undergoing coronary angiography, 205 (55.4%) PLWH vs. 165 (44.6%) uninfected controls had diagnoses of myocardial infarction (p=0.02). The location and severity of coronary stenoses did not differ significantly for PLWH vs. uninfected controls; mean maximal overall stenosis and mean maximal LAD, RCA, and LCx stenoses were 52.3% vs. 50.2% (p=0.52), 44.5% vs. 42.3% (p=0.48), 37.0% vs. 36.1% (p=0.78) and 31.4% vs. 31.6% (p=0.95) respectively. There was no significant difference in odds of having significant coronary stenosis for PLWH vs. uninfected controls (multivariable-adjusted OR 1.15, 95% CI 0.79-1.70). Among PLWH, peak HIV viral load was associated with borderline significantly greater odds of ≥50% coronary stenosis after adjustment for demographics, CVD risk factors, and HIV therapies (OR 1.07 per 10-fold greater peak HIV viral load, 95% CI 1.00-1.14, p=0.04), but lower Nadir CD4+ T cell count (&lt;200 vs. ≥200 cells/mm 3 ) was not (OR 1.05, 95% CI 0.74-1.48, p=0.79). Conclusions: There was no consistent or significant difference in severity of coronary artery stenosis among PLWH and uninfected controls undergoing invasive coronary angiography in the course of routine clinical care. Higher peak HIV viral load is associated with borderline significantly greater odds of having significant coronary stenosis among PLWH undergoing invasive coronary angiography.

Higher Anti-Cytomegalovirus Immunoglobulin G Concentrations Are Associated With Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy.

Cytomegalovirus (CMV) has been linked to higher risk of cardiovascular disease and mortality. We aimed to determine if CMV is associated with neurocognitive performance in adults infected with human immunodeficiency virus (HIV). In this cross-sectional analysis, anti-CMV immunoglobulin G (IgG) concentrations in blood and CMV DNA copies in blood and cerebrospinal fluid (CSF) were measured in stored specimens of 80 HIV-infected adults who were previously assessed with a comprehensive neurocognitive test battery. Thirty-eight were taking suppressive antiretroviral therapy (ART) and 42 were not taking ART. A panel of 7 soluble biomarkers was measured by immunoassay in CSF. Anti-CMV IgG concentrations ranged from 5.2 to 46.1 IU/mL. CMV DNA was detected in 7 (8.8%) plasma specimens but in no CSF specimens. Higher anti-CMV IgG levels were associated with older age (P = .0017), lower nadir CD4+ T-cell count (P < .001), AIDS (P < .001), and higher soluble CD163 (P = .009). Higher anti-CMV IgG levels trended toward an association with worse neurocognitive performance overall (P = .059). This correlation was only present in those taking suppressive ART (P = .0049). Worse neurocognitive performance remained associated with higher anti-CMV IgG levels after accounting for other covariates in multivariate models (model P = .0038). Detectable plasma CMV DNA was associated with AIDS (P = .05) but not with neurocognitive performance. CMV may influence neurocognitive performance in HIV-infected adults taking suppressive ART. Future clinical trials of anti-CMV therapy should help to determine whether the observed relationships are causal.

CNS-Targeted Antiretroviral Strategies: When Are They Needed and What to Choose.

Neurocognitive disorders are not uncommon in HIV-positive patients but their pathogenesis is multifactorial and incompletely understood. After excluding contributing comorbidities, several factors may impair neurocognition including severe immune suppression, incomplete antiviral efficacy, drugs' persistent immune activation, vascular abnormalities, and drugs' neurotoxicity. The effectiveness of targeted antiretroviral strategies on these risk factors is unknown. Recent studies support the idea that residual cerebrospinal fluid HIV RNA in the setting of plasma viral suppression is associated with compartmental immune activation but the link to neuronal damage is debated. Some authors have reported an incomplete antiviral efficacy in macrophage-derived cells but targeted antiretroviral regimen switches have not been performed. Additionally, improvements in neurocognition using drugs with better central nervous system penetration or maraviroc (associated with favorable immunological properties) have been observed in pilot studies. Trials evaluating specific interventions for cardiovascular health (including brain white matter abnormalities) and neurotoxicity of antiretrovirals are warranted. Central nervous system-targeted antiretroviral strategies are needed in patients with uncontrolled cerebrospinal HIV replication, and they may be suggested in subjects with low CD4 nadir, individuals carrying drug-resistant viruses, and those with compartmental immune activation.

Airflow limitation in people living with HIV and matched uninfected controls

IntroductionWhether HIV influences pulmonary function remains controversial. We assessed dynamic pulmonary function in people living with HIV (PLWHIV) and uninfected controls.MethodsA total of 1098 PLWHIV from the Copenhagen Co-morbidity in...

HIV-1 co-receptor tropism and liver fibrosis in HIV-infected patients.

BackgroundIn vitro, gp120 of both X4 and R5 HIV-1 strains activates human hepatic stellate cells, but if it can promote liver fibrosis in vivo is unknown. We aimed to evaluate if patients carrying X4 or R5 strains have a different liver fibrosis (LF) progression over time.MethodsA total of 1,137 HIV-infected patients in ICONA cohort (21% females, 7% HCV co-infected) with an available determination of HIV-1 co-receptor tropism (CRT), a Fibrosis-4 Index for Liver Fibrosis (FIB-4) <3.25 and at least one-year follow-up were included. CRT was assessed by gp120 sequencing on plasma RNA and geno2pheno algorithm (10% false positive rate) or by Trofile. LF was assessed by means of FIB-4. LF progression was defined as an absolute score increase or a transition to higher fibrosis stratum and/or occurrence of liver-related clinical events.ResultsA total of 249 (22%) patients carried X4 strains, which were associated with older age, lower CD4 count, lower nadir CD4, and intravenous drug use. Overall, X4 and R5 patients had similar baseline FIB-4 scores and similar mean FIB-4 slope after a median follow-up of 35 months. There was no difference between X4 and R5 for time to LF progression (p = 0.925). Estimated risk of LF at 24 months (95% CI) after baseline in X4 and R5 was 10.6% (8.3–12.9) and 9.9% (5.9–14.0), respectively. Age, HCV co-infection, diabetes, HIV-duration, HIV-RNA>100.000 cp/mL, antiretroviral therapy exposure were associated with LF progression at multivariate analysis.ConclusionsA slight LF progression over time was observed in HIV-infected patients. No difference was demonstrated for X4 and R5 HIV-1 strains in accelerating LF evolution.

Factors associated with urinary tract infections among HIV-1 infected patients.

BackgroundUrinary tract infections remain an important yet underinvestigated clinical problem among HIV infected patients. Here we analyze factors associated with its occurrence and the spectrum of bacterial pathogens identified in the group of patients followed at the HIV Out-Patient Clinic in Warsaw.MethodsClinic database collected all medical information on patients routinely followed since 1994 to 2015. All patients with available urine culture were included into analyses, only the first culture was included. In statistical analyses logistic regression models were used to identify factors associated with positive culture.ResultsIn total 608 patients had urine culture performed, 176 (28.9%) were females and 432 (71,1%) were males, 378 (62.2%) registered in care before/in 2007, 258 (42.4%) infected through homosexual contact. Median baseline lymphocyte CD4+ count was 385 (IQR:204–565) cells/μl and median nadir lymphocyte CD4+ count 197 (86–306) cells/μl. One hundred and eighteen patients were actively infected with HCV, as defined by positive real-time PCR. In total 141 (23.2%) patients had positive urine culture, the most common bacterial pathogen was E.coli (58.2%) and E. faecalis (12.8%). Patients with urinary tract infection were more likely to be female (51.8% vs. 22.1%, p<0.0001), infected through other than homosexual mode (80.1% vs. 50.7%, p<0.0001), with lower nadir CD4 count (139 vs. 221 cells/μl, p<0.0001) and lower baseline HIV RNA (4.02 vs. 4.35 log copies/ml, p = 0.01) and less likely to be HCV RNA positive (26.9% vs. 49.2%, p = 0.01). In multivariate regression model being registered before/in 2007 (OR = 2.10; [95%CI: 1.24–3.56]), infected through other than homosexual mode (2.05;[1.18–3.56]) and female gender (2.14;[1.33–3.44]) were increasing and higher nadir CD4+ count decreasing (0.92;[0.85–0.99]) the odds of urinary tract infection.ConclusionsWe have identified that almost one third of patients had urinary tract infections with non-typical bacterial pathogens. Population with increased odds of urinary tract infections are women, patients infected through other than homosexual contacts and those registered before 2007.

The Effect of Detectable HIV Viral Load among HIV-Infected Children during Antiretroviral Treatment: A Cross-Sectional Study.

The RNA viral load of human immunodeficiency virus (HIV) is initially used to determine the status of the HIV infection. The goal of therapy following treatment failure is to achieve and maintain virologic suppression. A detectable viral load may relate to the progression of HIV infection. A cross-sectional survey was conducted from January 2013 to December 2014 at the Bamrasnaradura Infectious Diseases Institute, Thailand. The aim was to determine the prevalence of detectable HIV viral load (dVL) and analyze the factors associated with post-dVL conditions that occur independently of a switch to a new antiretroviral agent. The prevalence of dVL was 27% (27 of 101). The mean ages of dVL and non-dVL children were 12.0 and 12.3 years, respectively. Age, sex, body mass index for age z-scores, previous tuberculosis disease history and parental tuberculosis history of both groups were not significantly different (p > 0.05). The prevalence of poor adherence (<95%), influenza-like illness (ILI) and opportunistic infections were higher in dVL than non-dVL children (p < 0.05). The mean nadir CD4 cell count during the study was lower in dVL than non-dVL children (646 compared to 867, respectively; p < 0.05). Other factors were not significant (all p > 0.05). In multivariable analysis, dVL was significantly associated with ILI (odds ratio (OR) = 9.6, 95% confidence interval (CI) = 1.3–69.4), adherence (OR = 0.195, 95% CI = 0.047–0.811) and nadir CD4 during the study (OR = 1.102, 95% CI = 1.100–1.305). The prevalence of dVL was 27% with this dVL among HIV-infected children found to be associated with ILI, poor adherence and lower nadir CD4 during the study.

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

Metabolic syndrome in HIV infected adults in Poland.

Metabolic syndrome (MS) is usually diagnosed based on the presence of abdominal obesity, elevated blood pres-sure (BP), elevated fasting plasma glucose, high serum triglycerides (TG), and low high-density lipoprotein (HDL) cholesterol levels. Whether HIV is associated with a higher prevalence of MS than in the general population remains unclear. The aim of the study was to determine the incidence of MS in the population of HIV-infected adults and its association with clinical, virological, and biochemical features. Two hundred and seventy HIV-infected Caucasian adult patients were enrolled in the study and evaluated based on clinical records in the years 2013-2015. Metabolic syndrome was diagnosed in 60 of 270 (22%) patients, 47 (24%) males and 13 (17%) females, mostly (72%) aged above 40 years. The percentage of patients with diagnosed MS in specific age groups in comparison to the general Polish population for females aged < 40 years was 7% vs. 4%, and males in the same age - 18% vs. 9%, for females aged 40-59 years - 47% vs. 24.4%, and males - 33% vs. 28.3%. Particular components of MS in the MS population were found as follows: body mass index > 30 kg/m2 in 29%, waist circumference exceeding 94 cm in men and 80 cm in woman - 87.5%, TG ≥ 150 mg/dL - 82%, HDL cholesterol < 40/50 mg/dL (males/females) - 42%, systolic/diastolic BP ≥ 130 mmHg/≥ 85 mmHg - 83%, and fasting glucose > 100 mg/dL - 42%. In stepwise multivariate logistic regression analysis, age (odds ratio [OR] 1.052, 95% con-fidence interval [CI] 1.018-1.088, p = 0.003) and nadir CD4 < 350 cells/mm3 (OR 3.576, 95% CI 1.035-12.355, p = 0.04) were associated with MS. Patients with MS compared with those without this disorder had low, intermediate, high, and very high cardiovascular risk in 10% vs. 23%, 73% vs. 70%, 7% vs. 5%, and 10% vs. 2%, respectively (p = 0.006). Prevalence of MS in the HIV-infected population is higher than in the general Polish population. Age and low nadir CD4 were found to be associated with MS.

Effects of antiretroviral treatment and nadir CD4 count in progression to cardiovascular events and related comorbidities in a HIV Brazilian cohort: a multi-stage approach

ABSTRACTThe use of highly active antiretroviral therapy has resulted in changes of comorbidity profile in people living with HIV (PLHIV), increasing non-AIDS-related events. The occurrence of cardiovascular events is greater in PLHIV, but the mechanism responsible for it is still controversial. This article aimed to investigate factors associated with the progression to cardiovascular events in PLHIV using HAART. A 15-years cohort study with 1135 PLHIV was conducted in Rio de Janeiro-Brazil. Clinical progression was stratified in five states: No comorbidities (s1), arterial hypertension (s2), lipid abnormalities (s3), hypertension and lipid abnormalities (s4) and major cardiovascular events (stroke, coronary artery disease, thrombosis or death) (s5). Semi-Markov models evaluated the effects of cardiovascular traditional factors, treatment and clinical covariates on transitions between these states. Hazard Ratios (HR) and 95% confidence intervals (CI) were provided. In addition to traditional factors (age, sex, educational level and skin color), the development of one comorbidity (lipid abnormalities or hypertension) increased in patients with low nadir CD4 (<50 cells/mm3), (HR = 1.59, CI 1.11–2.28 and 1.36, CI 1.11–1.66, respectively). The risk to experience a second comorbidity (s3→s4) increased 75% with low nadir CD4. Age was the only factor that increased the risk of major cardiovascular events once having lipid abnormalities with or without hypertension (s3,s4→s5). The prolonged use of certain antiretroviral drugs (abacavir, didanosine, ritonavir, lopinavir, amprenavir and fosamprenavir) increased the risk of direct transition (s1→s5) to major cardiovascular events (HR = 5.29, CI 1.16–24.05). This analysis suggests that prolonged use of certain antiretroviral drugs led directly to major cardiovascular events, while low nadir CD4 only affected the occurrence of lipid abnormalities and hypertension. Management strategies, including rational use of complex exams (such as, computed-tomography angiography), statins and antihypertensives, should be developed based on the distinct roles of antiretroviral use and of HIV infection itself on the progression to cardiovascular events.

Rapid CD4 decline prior to antiretroviral therapy predicts subsequent failure to reconstitute despite HIV viral suppression.

HIV-1 infection is characterized by loss of CD4T cells, leading to immunodeficiency. Initiation of antiretroviral therapy (ART) results in suppression of the viral load and increased CD4 counts. Both viral and host factors determine CD4 cell responses to ART with approximately 15-30% of individuals having suboptimal increase of CD4T cell count, most commonly due to lack of compliance to ART. A smaller fraction of patients will have immune reconstitution failure and suboptimal CD4 increase despite suppression of HIV replication, and these individuals are at risk for adverse health outcomes. We sought to characterize the factors associated with decreased immunological response among Manitoba's HIV patient population. This retrospective case-control study included HIV patients with immune reconstitution failure despite suppression of HIV replication by ART. The immune reconstitution failure was defined by CD4 cell count increase from baseline of less than 100 CD4 cells/mm3 or lack of increase to above 200 CD4 cells/mm3 within one year of viral load suppression. Age and nadir CD4 cell counts are known risk factors associated with immune reconstitution failure. We chose controls (Patients with immune reconstitution success) of similar age and CD4 nadir cell with cases (Patients with immune reconstitution failure). We explored the potential effects of gender, HLA type, presence of co-infection, ethnicity, ART type, and rate of pre-treatment CD4 decline among cases and controls. Of more than 550 patients followed by our HIV clinic, 42 individuals met our definition of immune reconstitution failure and they were assigned to the cases group. 31 patients, comprising a range of ages and CD4 nadirs similar to those of the cases, were assigned to the control group. Our primary analysis was a regression model, predicting post-ART change in CD4 over time. After controlling for age and nadir CD4 cell counts, the only potential predictor that appears consistently associated with the rate of post-ART rise in CD4 over time in our cohort, regardless of the other variables that we have controlled for, is the rate of decline in CD4 pre-ART initiation. Several factors have been variably correlated with immune reconstitution failure of CD4 T cell count. Age and low CD4 nadir are factors previously shown to correlate with immune reconstitution failure; and we have controlled for them in our study. Another possible predictor is the rate of decline in CD4 pre-ART, which can serve as an additional marker of reconstitution failure and necessitate prioritizing individuals to ART initiation or identification of a subset of individuals that may be targeted for future adjunct strategies to improve immune recovery.

Neurocognitive Impairment in a Chronically Well-Suppressed HIV-Infected Population: The Dutch TREVI Cohort Study.

We assessed the value of screening for cognitive abnormalities in a chronically infected HIV population (N = 388) and investigated the association with clinical correlates. The mean age was 48 years (±11), the majority of the patients were male (89%), the median duration of infection was 6 years [interquartile range (IQR) = 2-12], the median CD count was 600 (IQR = 450-780), and 326 (84%) had a viral load below 200 copies/mL. Screening for cognitive complaints was applied using the three Simioni questions and the international HIV dementia scale (iHDS). Neuropsychological assessment (NPA) included 13 well-validated tests assessing motor speed, concentration, and memory. A total of 69 patients completed the NPA. CD4 (nadir), viral load, combination antiretroviral therapy (cART) duration, and the presence of comorbidities were evaluated for associations with NPA result. A total of 127 (33%) reported cognitive complaints during screening. The sensitivity and specificity of the Simioni questions were 82% and 24%, respectively. Adding the iHDS resulted in a sensitivity of 50% and a specificity of 73%. A CD4 nadir count <50 cells/m3 was associated with an abnormal NPA (p = 0.01). Comorbidities were more prevalent in patients with an abnormal NPA, although not statistically significant (p = 0.276). Age, current CD4, viral load, and cART duration were not associated with abnormal NPA. The authors conclude that current screening strategies are insufficient in detecting HIV-associated neurocognitive disorder. A low CD4 nadir is associated with poor neurocognitive outcome in HIV.

HIV-associated executive dysfunction in the era of modern antiretroviral therapy: A systematic review and meta-analysis

ABSTRACTObjective: While some reports suggest that HIV+ individuals continue to display executive function (EF) impairment in the era of cART, findings have been contradictory and appear to differ based on the aspect of EF being measured. To improve the understanding of how discrete executive abilities may be differentially affected or spared in the context of HIV infection, we conducted a systematic review and meta-analysis to (a) determine whether and to what extent HIV+ adults experience deficits in EFs, and (b) understand how demographic and clinical characteristics may modify the associations between HIV infection and executive abilities.Method: Studies comparing HIV+ and HIV-uninfected groups on measures of working memory, set-shifting, inhibition, decision-making, and apathy between 2000 and 2017 were identified from three databases. Effect sizes (Cohen’s d) were calculated using inverse variance weighted random effects models. Meta-regression was used to examine the moderating effect of demographic and clinical variables.Results: Thirty-seven studies (n = 3935 HIV+; n = 2483 HIV-uninfected) were included in the meta-analysis. Pooled effect sizes for deficits associated with HIV infection were small for domains of set-shifting (d = −0.34, 95% CI [−0.47, −0.20]) and inhibition (d = −0.31, 95% CI [−0.40, −0.21]), somewhat larger for measures of decision-making (d = −0.41, 95% CI [−0.53, −0.28]) and working memory (d = −0.42, 95% CI [−0.59, −0.29]), and largest for apathy (d = −0.87, 95% CI [−1.09, −0.66]). Meta-regression demonstrated that age, sex, education, current CD4 count, and substance dependence differentially moderated the effects of HIV infection on specific EFs. However, lower nadir CD4 count was the only variable associated with greater deficits in nearly all EF domains.Conclusions: Our results suggest that discrete domains of EF may be differentially affected by HIV infection and moderating demographic and clinical variables. These findings have implications for the development of targeted cognitive remediation strategies.

Hypertension in HIV-Infected Adults Compared with Similar but Uninfected Adults in China: Body Mass Index-Dependent Effects of Nadir CD4 Count.

Hypertension is a growing problem in the HIV population. The relationship between low nadir CD4 count and hypertension in the HIV-infected population has been reported. However, the effect of nadir CD4 on hypertension due to a different body mass index (BMI) is yet to be fully elucidated. In this cross-sectional study, 345 HIV-infected participants aged ≥40 years were recruited. They were frequency matched and compared with age, sex, and education with HIV-uninfected adults (n = 345). Hypertension prevalence was lower in HIV-infected than in HIV-uninfected participants (23.8% vs. 31.9%; p = .011), but this association was not significant after adjusting for potential confounders. Among HIV-infected individuals, older age, overweight, with a family history of cardiovascular diseases, and nadir CD4 count <50 cells/μl were independently associated with hypertension. Stratifying individuals with BMI category revealed that nadir CD4 count-regardless if it was operationalized as a dichotomous variable (<50 cells/μl) or continuous variable-was found to be associated with hypertension among individuals who were underweight and obese, but not among those who were normal weight and overweight. Among HIV-uninfected individuals, older age and having a waist circumference above cutoff were significantly associated with hypertension. This is one of the first studies to demonstrate that the association of nadir CD4 and hypertension is observed in underweight and obese HIV-infected patients. While these results suggest that the relationship between nadir CD4 count and hypertension might be mediated by body weight, future longitudinal studies will be needed to validate the findings, including its causal pathways.