Lower Nadir CD4 Count Research Articles

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.

Neurobehavioral Disturbances During Acute and Early HIV Infection.

Acute and early human immunodeficiency virus infection (AEH) is accompanied by neuroinflammatory processes as well as impairment in neurocognitive and everyday functions, but little is known about the frequency and clinical correlates of the neurobehavioral disturbances during this period. We compared pre-seroconversion with current levels of apathy, disinhibition, and executive dysfunction; we also examined everyday function and HIV disease correlates of neuropsychiatric impairment in individuals with AEH. In this study, 34 individuals with AEH and 39 HIV-seronegative participants completed neuromedical and neuropsychological assessments, a structured psychiatric interview, and the apathy, disinhibition, and executive dysfunction subscales of the Frontal Systems Behavioral Scale. Independent of any substance use and mood disorders, the AEH group had significantly higher levels of current apathy and executive dysfunction than the controls, but not greater disinhibition. Retrospective ratings of pre-seroconversion levels of apathy, disinhibition, and executive dysfunction were all higher in the AEH group than the controls. After seroconversion, the AEH cohort had increases in current apathy and executive dysfunction, but not disinhibition. In the AEH cohort, higher current global neurobehavioral dysfunction was significantly associated with lower nadir CD4 counts, slowed information processing speed, and more everyday function problems. These data suggest that individuals who have recently acquired HIV experienced higher-than-normal premorbid levels of neurobehavioral disturbance. Apathy and executive dysfunction are exacerbated during AEH, particularly in association with lower CD4 counts.

Determinants of IL-6 levels during HIV infection.

IntroductionElevated IL-6 levels have been linked to increased risk of cardiovascular disease (CVD), cancer and death. Compared to the general population, treated HIV+ persons have 50–100% higher IL-6 levels, but few data on the determinants of IL-6 levels during HIV infection currently exist.Material and MethodsParticipants in three international HIV trials (SMART, ESPRIT and SILCAAT) with IL-6 plasma levels measured at baseline were included (N=9864). Factors independently associated with log2-transformed IL-6 level were identified by multivariate linear regression; exponentiated estimates corresponding to fold differences (FDs) in IL-6 were calculated. Demographics (age, gender, race, BMI) and HIV-specific variables (nadir and entry CD4 counts, HIV-RNA, use of different ART regimens) were investigated in all three trials. In SMART (N=4498), smoking, comorbidities (CVD, diabetes, hepatitis B/C [HBV/HCV]), HDL-cholesterol, renal function (eGFR) and educational level were also assessed.ResultsDemographics associated with higher IL-6 were older age (FD [95% CI]: 1.09 [1.08–1.11] per 10 yr) and higher BMI (1.02 [1.01–1.04] per 5 kg/m2), whereas black race was associated with reduced IL-6 (0.96 [0.93–0.99]). As for HIV variables, patients not receiving ART (1.36 [1.29–1.43]) and with higher HIV-RNA (1.24 [1.01–1.52] for >100,000 vs. ≤500 copies/mL) had increased IL-6. Participants taking protease inhibitors (PI) had higher IL-6 (1.14[1.09–1.19]). Higher nadir CD4 count (0.98 [0.97–0.99]/100 cells/µL) was related to lower IL-6. All evaluated comorbidities were related to higher IL-6; FDs in IL-6 were 1.08 [1.04–1.12] for smoking, 1.12 [1.02–1.24] for CVD, 1.07 [1.00–1.16] for diabetes and 1.12 [1.02–1.24] for HBV (1.15 [1.02–1.30]) and 1.53 [1.45–1.62] for HCV. IL-6 increased with decreasing eGFR (0.98 [0.97–1.00]/10 mL/min) and HDL-cholesterol (0.98 [0.96–0.99]/10 mg/mL). Lower education was related to higher IL-6 (1.09 [1.03–1.15] for high school vs. bachelor's degree).ConclusionsHigher IL-6 levels were associated with older age and non-black race, higher BMI and lower HDL-cholesterol, ongoing HIV replication, low nadir CD4 counts, comorbidities and decreased renal function. This suggests that there are multiple causes of inflammation in treated HIV infection. A possible contribution from PI use was also observed. Contribution from inflammation to explain variation in clinical outcomes for these factors should be investigated.

Factors Associated With Delayed Hepatitis B Viral Suppression on Tenofovir Among Patients Coinfected With HBV-HIV in the CNICS Cohort

Despite widespread use in HIV and hepatitis B virus (HBV) infection, the effectiveness of tenofovir (TDF) has not been studied extensively outside of small cohorts of coinfected patients with HBV-HIV. We examined the effect of prior lamivudine (3TC) treatment and other factors on HBV DNA suppression with TDF in a multisite clinical cohort of coinfected patients. We studied all patients enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort from 1996 to 2011 who had chronic HBV and HIV infection, initiated a TDF-based regimen continued for ≥ 3 months and had on-treatment HBV DNA measurements. We used Kaplan-Meier curves and Cox-proportional hazards to estimate time to suppression (HBV DNA level <200 IU/mL or <1000 copies/mL) by selected covariates. Among 397 coinfected patients on TDF, 91% were also on emtricitabine or 3TC concurrently, 92% of those tested were hepatitis B e antigen positive, 196 (49%) had prior 3TC exposure; 192 (48%) achieved HBV DNA suppression over a median of 28 months (interquartile range: 13-71). Median time to HBV DNA suppression was 17 months for those who were 3TC-naive and 50 months for those who were 3TC exposed. After controlling for other factors, prior 3TC exposure, baseline HBV DNA level >10,000 IU/mL, and lower nadir CD4 count were independently associated with decreased likelihood of HBV DNA suppression on TDF. These results emphasize the role of prior 3TC exposure and immune response on delayed HBV suppression on TDF.

Prevalence and Predictors of Elevated Aspartate Aminotransferase-to-Platelet Ratio Index in Latin American Perinatally HIV-infected Children

Chronic liver disease has emerged as an important problem in adults with longstanding HIV infection, but data are lacking for children. We characterized elevated aspartate aminotransferase-to-platelet ratio index (APRI), a marker of possible liver fibrosis, in perinatally HIV-infected children. The National Institute of Child Health and Human Development International Site Development Initiative enrolled HIV-infected children (ages 0.1-20.1 years) from 5 Latin American countries in an observational cohort from 2002 to 2009. Twice yearly visits included medical history, physical examination and laboratory evaluations. The prevalence (95% confidence interval) of APRI > 1.5 was calculated, and associations with demographic, HIV-related and liver-related variables were investigated in bivariate analyses. APRI was available for 1012 of 1032 children. APRI was >1.5 in 32 (3.2%, 95% confidence interval: 2.2%-4.4%) including 2 of 4 participants with hepatitis B virus infection. Factors significantly associated with APRI > 1.5 (P < 0.01 compared with APRI ≤ 1.5) included country, younger age, past or current hepatitis B virus, higher alanine aminotransferase, lower total cholesterol, higher log10 current viral load, lower current CD4 count, lower nadir CD4 count, use of hepatotoxic nonantiretroviral (ARV) medications and no prior ARV use. Rates of APRI > 1.5 varied significantly by current ARV regimen (P = 0.0002), from 8.0% for no ARV to 3.2% for non-protease inhibitor regimens to 1.5% for protease inhibitor-based regimens. Elevated APRI occurred in approximately 3% of perinatally HIV-infected children. Protease inhibitor-based ARVs appeared protective whereas inadequate HIV control appeared to increase risk of elevated APRI. Additional investigations are needed to better assess potential subclinical, chronic liver disease in HIV-infected children.

A Brief and Feasible Paper-Based Method to Screen for Neurocognitive Impairment in HIV-Infected Patients

Practical screening methods are necessary to detect neurocognitive impairment (NCI) in HIV-infected patients. We aimed to find a brief and feasible paper-based tool to facilitate the diagnosis of an HIV-associated neurocognitive disorder. A total of 106 HIV-infected outpatients with variable clinical characteristics were recruited in a multicenter investigation. NCI was diagnosed using a standardized neuropsychological tests battery (7 areas, 21 measures, ∼2 hours). Multiple score combinations were compared to find a paper-based method that took ≤10 minutes to apply. The presence of NCI was considered the gold standard for comparisons, and the sensitivity and specificity were calculated. Subjects were mostly middle-aged (median, 44 years) men (87%) on antiretroviral treatment. NCI was detected in 51 individuals (48%) and was associated with lower nadir CD4 count (P < 0.001), receiving antiretroviral therapy (P = 0.004), fewer years of education (P = 0.009), and presence of comorbidities (P < 0.001). The score combination that showed the highest sensitivity (74.5%) and specificity (81.8%) detecting NCI included 3 measures of attention/working memory, executive functioning, and verbal fluency (part A of Trail Making Test, part B of Trail Making Test, and Controlled Oral Word Association Test scores). A broader paper-based selection of measures covering 7 areas indicated a sensitivity of 100% and a specificity of 96.3% (7 measures, ∼35 minutes). The combination of the 3 measures presented in this study seems to be a rapid and feasible screening mean for NCI in HIV-infected patients. This approach, combined with screening for potential comorbidities and daily functioning interference, could help in the initial stages of a HIV-associated neurocognitive disorder diagnosis and in settings with limited access to neuropsychological resources.

Increased Ocular Lens Density in HIV-Infected Individuals With Low Nadir CD4 Counts in South Africa

HIV infection is thought to be associated with an increased risk of age-related morbidity and premature aging. Lens density increases with age and may function as a biomarker of aging. The relationship of lens density measurements with clinical and demographic characteristics in HIV-infected individuals in comparison with a matched population of HIV-seronegative individuals was investigated. Case-control study of 490 adults aged greater than or equal to 30 years composed of 242 HIV-infected adults and 248 age- and sex-matched HIV-seronegative individuals. Lens density was assessed using lens densitometry (Pentacam) imaging. Measurements were divided into quartiles, and comparison of HIV status and HIV-related factors was assessed by multivariate and multinomial logistic regression. The mean age was 41.2 years in HIV-infected adults and 42.3 years in HIV-seronegative individuals (P = 0.14). Of the HIV-infected adults, 88% were receiving antiretroviral therapy (ART) (median duration, 58 months), and within this group, their median CD4 count was 468 cells per microliter and 84% had undetectable viral load. Although adjusted lens densities were similar by HIV serostatus, participants on ART and who had nadir CD4 counts less than 200 cells per microliter had a higher risk of high lens density compared with HIV-seronegative individuals (P trend = 0.04). Lens density was weakly associated with detectable HIV viremia despite ART, but not with current CD4 count. HIV-infected individuals on ART with nadir CD4 counts <200 cells per microliter had increased risk of higher lens density. Lens density may represent a novel biomarker of aging, providing insight into accelerated aging trajectories in HIV infection.

Human Immunodeficiency Virus Infection Heightens Concurrent Risk of Functional Dependence in Persons With Long-Term Methamphetamine Use

Disability among long-term methamphetamine (MA) users is multifactorial. This study examined the additive adverse impact of human immunodeficiency virus (HIV) infection, a common comorbidity in MA users, on functional dependence. A large cohort of participants (N = 798) stratified by lifetime MA-dependence diagnoses (ie, MA+ or MA-) and HIV serostatus (ie, HIV+ or HIV-) underwent comprehensive baseline neuromedical, neuropsychiatric, and functional research evaluations, including assessment of neurocognitive symptoms in daily life, instrumental and basic activities of daily living, and employment status. Independent, additive effects of MA and HIV were observed across all measures of functional dependence, independent of other demographic, psychiatric, and substance-use factors. The prevalence of global functional dependence increased in the expected stepwise fashion across the cohort, with the lowest rates in the MA-/HIV- group (29%) and the highest rates in the MA+/HIV+ sample (69%). The impact of HIV on MA-associated functional dependence was moderated by nadir CD4 count, such that polysubstance use was associated with greater disability among those HIV-infected persons with higher but not lower nadir CD4 count. Within the MA+/HIV+ cohort, functional dependence was reliably associated with neurocognitive impairment, lower cognitive reserve, polysubstance use, and major depressive disorder. HIV infection confers an increased concurrent risk of MA-associated disability, particularly among HIV-infected persons without histories of immune compromise. Directed referrals, earlier HIV treatment, and compensatory strategies aimed at counteracting the effects of low cognitive reserve, neurocognitive impairment, and psychiatric comorbidities on functional dependence in MA+/HIV+ individuals may be warranted.

Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors

BackgroundMetabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined.MethodsUntargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software.ResultsA 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction.ConclusionsLipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.

33. Gradually decreasing anal cancer incidence in the HIV+ population in the Netherlands after a decade of cART

Background Anal cancer incidence has been increasing in the combined antiretroviral therapy (cART) era in HIV+ patients. In this study we surveyed trends in anal cancer incidence between 1995 and 2012, and analysed a range of potential risk factors. Methods: We retrieved data for all patients diagnosed with anal cancer from the Dutch HIV observational cohort (ATHENA) database. Incidence rates were calculated per 100 000 person-years of follow-up (FU), for the whole period of 18 years, and per 2-year blocks. Potential risk factors were analysed in a uni- and multivariable Cox proportional hazard model. Results: For all HIV+ patients, men who have sex with men (MSM), and heterosexual men and women, respectively, the incidence of anal cancer was 83 (95% CI 70–99), 116 (95% CI 95–140), 44 (95% CI 21–83) and 12 (95% 3–30) per 100 000 person-years of FU. In 2005–2006, a peak in incidence rates was observed of 114 (95% CI 74–169) in the total HIV population and 168 (95% CI 103–259) among HIV+ MSM, followed by a decrease to 72 (95% CI 42–113) and 100 (95% CI 56–164), respectively, in 2011–2012. Low nadir CD4 (&lt;110), alcohol abuse and smoking were significantly associated with anal cancer in MSM, with hazard ratios (HR) of 2.41 (95%CI 1.5–3.89), 2.23 (95% CI 1.28–3.89) and 1.60 (95% CI 1.07–2.41), respectively. Conclusions: Anal cancer remains a serious problem in predominantly HIV+ MSM; however, it seems that incidence rates are levelling off. A low nadir CD4 count, alcohol abuse and smoking are risk factors for the development of anal cancer.

Impact of antiretroviral therapy (ART), immunosuppression and viraemia on lipid levels: the D:A:D study

Purpose of the studyTo investigate the impact of ART, HIV viremia and immunosuppression on triglyceride (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL‐C) levels.MethodsWe considered the cross‐sectional associations between TG, TC and HDL‐C (mmol/l; first available measurement on/after enrolment in the D:A:D study) and use of ART, HIV viral load (VL; copies/ml), and CD4 count (cells/mm3) measured at the same time. TG was log10 transformed to ensure normality. Analyses were performed using linear regression and adjusted for other factors known to impact lipid levels (table footnote). ART and VL status were combined (off ART&amp;VL &gt;100,000, off ART&amp;VL &lt;100,000, on ART&amp;VL &lt;500, on ART&amp;VL &gt;500), current and nadir CD4 count were categorised as &lt;200, 200–349, 350–499 and &gt;500.Summary of results44,322/49,734 participants in the D:A:D Study (89.1%) contributed a TG measurement (median; IQR 1.52; 1.00–2.45), 45,169 (90.8%) a TC measurement (4.80; 4.00–5.70) and 38,604 (77.6%) a HDL‐C measurement (1.12; 0.90–1.40). Most participants were male (74%), of white ethnicity (51%), without AIDS (78%), were not receiving lipid‐lowering drugs (4%) and were ART experienced (61%) with 47% previously exposed to PIs, 61% previously exposed to NRTIs and 29% previously exposed to NNRTIs. The median (IQR) age, current CD4 count and CD4 nadir were 38 (36–45) years, 400 (242–590) cells/µl and 240 (100–410) cells/µl respectively. Compared to those on ART with a suppressed VL, all lipids were lower for those off ART (Table); non‐suppressive ART was also associated with lower TC and HDL‐C levels (no impact on TG). A low current CD4 count was associated with lower lipid levels, whereas a low nadir CD4 count was associated with higher TC and TG levels. Prior AIDS diagnosis was associated with higher TG and TC, but lower HDL‐C levels. Impact of ART, immunosuppression and viraemia, on TG, TC and HDL‐C (mmol/l) Average impact on log10TG*† Average inpact on TC* Average impact on HDL‐C* ART and VL Off ART … VL≥100000 −0.09 (−0.10,−0.08) &lt;0.001 −0.55 (−0.60,−0.51) &lt;0.001 −0.14 (−0.16,−0.13) &lt;0.001 Off ART … VL&lt;100000 −0.04 (−0.06,−0.03) &lt;0.001 −0.85 (−0.91,−0.78) &lt;0.001 −0.31 (−0.33,−0.29) &lt;0.001 On ART … VL&lt;500 Ref Ref Ref On ART … VL≥500 0.00 (−0.01, 0.00) 0.38 −0.40 (−0.44,−0.36) &lt;0.001 −0.16 (−0.17,−0.15) &lt;0.001 CD4 count &lt;200 −0.03 (−0.04,−0.02) &lt;0.001 −0.33 (−0.39,−0.28) &lt;0.001 −0.04 (−0.06,−0.02) &lt;0.001 200–349 −0.02 (−0.03,−0.01) &lt;0.001 −0.11 (−0.15,−0.06) &lt;0.001 0.00 (−0.01, 0.02) 0.72 350–499 Ref Ref Ref 500+ 0.04 (0.03, 0.04) &lt;0.001 0.12 (0.08, 0.16) &lt;0.001 −0.02 (−0.03,−0.00) 0.02 Nadir CD4 Count &lt;200 0.07 (0.06, 0.08) &lt;0.001 0.19 (0.14, 0.24) &lt;0.001 −0.05 (−0.06,−0.03) &lt;0.001 200–349 0.02 (0.01, 0.03) &lt;0.001 0.01 (−0.03, 0.06) 0.57 −0.03 (−0.05,−0.02) &lt;0.001 350–499 Ref Ref Ref 500 + 0.00 (−0.02, 0.01) 0.33 0.03 (−0.02, 0.09) 0.23 0.04 (0.02, 0.06) &lt;0.001 Prior AIDS 0.05 (0.05, 0.06) &lt;0.001 0.11 (0.08, 0.15) &lt;0.001 −0.03 (−0.04,−0.01) &lt;0.001 estimates included are mutually adjusted for each other and for the following demographic variables: age; gender; mode of infection; ethnicity; body mass index; smoking; family history of CVD; diabetes; use of lipid lowering drugs; co‐infection with hepatitis C; participating cohort; and year of entry into study. TG is log10 transformed. Thus, the results presented for TG reflect relative rather than absolute effects. For example, lipid levels for those off ART … VL ≥100000 are 9% lower than those on ART … VL &lt; 500. ConclusionAlthough specific drug classes were not considered, lipid levels are considerably higher in those on a suppressive ART regimen. The higher TC/TG and lower HDL‐C levels seen among those with low nadir CD4 count and with a prior AIDS diagnosis suggests severe immunosuppression may be associated with dyslipidaemia over the long‐term.

Lung cancer in HIV‐infected patients

PurposeSeveral studies have shown that HIV patients are at higher risk of lung cancer. Our aim is to analyse the prevalence and features of lung cancer in HIV-infected patients.MethodsThe clinical charts of 4,721 HIV-infected patients seen in three hospitals of southeast Spain (study period 1992–2012) were reviewed, and all patients with a lung cancer were analysed.ResultsThere were 61 lung cancers, giving a prevalence of 1.2%. There was a predominance of men (82.0%), and smokers (96.6%; mean pack-years 35.2), with a median age of 48.0 (41.7–52.9) years, and their distribution according to risk group for HIV was: intravenous drug use 58.3%, homosexual 20.0%, and heterosexual 16.7%. Thirty-four (56.7%) patients were Aids cases, and 29 (47.5%) had prior pulmonar events: tuberculosis 16, bacterial pneumonia 9, and P. jiroveci pneumonia 4. The median nadir CD4 count was 149/mm3 (42–232), the median CD4 count at the time of diagnosis of the lung cancer was 237/mm3 (85–397), and 66.1%<350/mm3. 66.7% were on ART, and 70% of them had undetectable HIV viral load. The most common histological types of lung cancer were adenocarcinoma and epidermoid, with 24 (40.0%) and 23 (38.3%) cases, respectively. There were 49 (80.3%) cases with advanced stages (III and IV) at diagnosis. The distribution of treatments was: only palliative 23 (39.7%), chemotherapy 14 (24.1%), surgery and chemotherapy 8 (13.8%), radiotherapy 7 (12.1%), surgery 4 (6.9%), and other combined treatments 2 (3.4%). Forty-six (76.7%) patients died, with a median survival time of 3 months. The Kaplan-Meier survival rate at 6 months was 42.7% (at 12 months 28.5%).ConclusionsThe prevalence of lung cancer in this cohort of HIV-patients is high. People affected are mainly men, smokers, with transmission of HIV by intravenous drug use, and around half of them with prior opportunistic pulmonary events. Most patients had low nadir CD4 count, and were immunosuppressed at the time of diagnosis. Adenocarcinoma is the most frequent histological type. The diagnosis is usually made at advanced stages of the neoplasm, and mortality is high.

HBV and neurological impairment in HIV‐infected patients

ObjectiveHIV can affect CNS in early stages of disease and determine neurological impairment. HBV DNA was found in CSF of HIV co‐infected patients, but little is known about the neurotropic character of this virus. Here we assessed the degree of association between HBV infection and neurological impairment in a large cohort of long‐term survivors, HIV‐infected patients that experienced multiple therapeutic schemes over time.MethodsA total of 462 HIV‐1‐infected patients were retrospectively followed up for 10 years for HBV infection and neurological impairment. The patients were tested for immune (flow cytometry) and virological parameters of HIV infection (Roche Amplicor, version 1.5/ COBAS AmpliPrep/COBAS TaqMan HIV‐1 test) and for HBV infection markers (HBsAg, anti HBc: Murex Biotech ELISA tests). Many of these patients have experienced between one and six regimens such as: 2 NRTIs, 3 NRTIs, 2 NRTIs+1 NNRTI, 1 NRTI+1 NNRTI+1 PI, 2 NRTIs+2 PIs.ResultsAfter 10 years 29.87% of the patients presented neurological impairment. Out of them 56.52% were HBV‐infected. The prevalence of HIV encephalopathy (HE) in our studied cohort was 22.7% and 50.4% of these patients were HBV‐infected. The median HIV diagnosis age was 7 and the median age of HE diagnosis was 10. In order to establish a possible correlation between HBV infection and HE we first reviewed and excluded the main risk factors associated with HE at the moment of diagnosis: low weight, anemia, constitutional symptoms, low CD4+count, high plasma HIV‐RNA load. No patient was infected with HCV. The groups of patients that presented HE and HBsAg and HE without HBsAg were balanced regarding sex, number of deceased patients, number of class C3 patients, but the patients in first group presented lower CD4 values at HE diagnosis vs patients from second group 2: 44.5 vs 95 cells/µL, p=0.3; lower nadir CD4 count: 38 vs 51 cell/µL, p=0.1; and slightly higher HIV viral load: 5.2 vs 5 log10 copies/mL, p = 0.2. There were only 53 patients that presented at the same time HE and HBV infection and the majority, 78.69%, were first infected with HBV.ConclusionsIn our studied cohort HBV infection was associated with HE but further studies are needed to prove HBV neurotropic potential. Absolute CD4 nadir count and class C3 are proved to be strong predictors of HE in HIV‐infected patients even after several changes in antiretroviral therapy schemes.

Predictors of symptomatic HIV‐associated neurocognitive disorders in universal health care

The aim of the study was to determine the risk factors predictive of symptomatic HIV-associated neurocognitive disorders (sHAND) among HIV-infected patients receiving active medical care. Baseline demographic and clinical characteristics were analysed in patients with sHAND (HIV-associated dementia and minor neurocognitive disorder) in a population-based longitudinal cohort of HIV-infected patients with access to universal health care, including combination antiretroviral therapy (cART) from 1999 to 2008. Variables evaluated for their association with sHAND included age and ethnicity, survival duration with HIV-1 infection, vascular disease risk factors, and laboratory indices such as blood CD4 T-cell count at its nadir and at cART initiation, using both univariable and multivariable logistic regression models. A total of 1320 patients were investigated, including the patients diagnosed with sHAND (n = 90) during the study period. In univariable analyses, increased age, increased length of survival with HIV, low nadir CD4 and CD8 T-cell counts, high baseline viral load (> 1,000,000 HIV-1 RNA copies/mL), and African origin were predictive of a diagnosis of sHAND (P < 0.05). In multivariable analysis, increased age, increased length of survival, low nadir CD4 T-cell counts, and high baseline viral load remained predictive of sHAND (P < 0.05). Remarkably, CD4 T-cell counts at cART initiation, hepatitis C virus coinfection, and vascular disease risk factors failed to predict sHAND in both analyses. Increased age and survival duration, lower nadir CD4 T-cell counts, and higher baseline viral load were consistent predictors of the development of sHAND among persons with HIV/AIDS in universal health care, underscoring the importance of attention to these variables in clinical care.

Eosinophilia: clinical significance in HIV-infected individuals

This study was conducted to determine the relationship between eosinophilia and parasitic infection in HIV-infected individuals. HIV-positive patients attending an HIV clinic in Birmingham were recruited and classified as either eosinophilic (>400 eosinophils/mm(3)) or non-eosinophilic. A demographic and parasitic risk history was taken and clinical examination was performed. Urine and stool were examined for parasites, and blood samples taken for parasite serology. A total of 266 patients (96 eosinophilic and 170 non-eosinophilic) were recruited. Of 64 eosinophilic patients who had a stool examination, one (1.6%) was positive for both Strongyloides larvae and schistosomal eggs. Urine microscopy was negative in the 245 patients (88 eosinophilic, 157 non-eosinophilic) from whom a sample was available. Two hundred and sixty-three patients underwent serological investigation (96 eosinophilic and 167 non-eosinophilic): 13 (4.9%) were positive for schistosomiasis and three (1.1%) positive for Strongyloides. A significant association between eosinophilia and positive schistosomal serology was found (P = 0.003): 11 (10.5%) were eosinophilic patients, while only four (2.3%) were non-eosinophilic patients. Eosinophilia was associated with a low nadir CD4 count (P = 0.021) and prior AIDS-defining illness (P = 0.041). In all, 7.8% of patients from a developing country and 5.3% of patients from a developed country with a travel history had positive parasitic serology. Eosinophilia in HIV-infected patients was significantly associated with positive serology for schistosomiasis, low nadir CD4 count and prior AIDS-defining illness. Geographical exposure is also an important determinant of positive parasitic serology.

Determinants of incident chronic kidney disease and progression in a cohort of HIV‐infected persons with unrestricted access to health care

As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use (IDU). Incident CKD was defined as an estimated glomerular filteration rate (eGFR) <60 ml/min/1.73 m(2) for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Rates were calculated per 1000 person-years (PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. Among 3360 participants [median age 29 years; 92% male; 44% African American (AA)] contributing 23,091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval (CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/μL, hazard ratio (HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/μL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/μL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/μL], and HIV diagnosis in the pre-highly active antiretroviral therapy (HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD.

Effects of HIV and Early Life Stress on Amygdala Morphometry and Neurocognitive Function

Both HIV infection and high levels of early life stress (ELS) have been related to abnormalities in frontal-subcortical structures, yet the combined effects of HIV and ELS on brain structure and function have not been previously investigated. In this study we assessed 49 non-demented HIV-seropositive (HIV+) and 47 age-matched HIV-seronegative healthy control (HC) adults. Levels of ELS exposure were quantified and used to define four HIV-ELS groups: HC Low-ELS (N = 20); HC High-ELS (N = 27); HIV+ Low-ELS (N = 24); HIV+ High-ELS (N = 25). An automated segmentation tool measured volumes of brain structures known to show HIV-related or ELS-related effects; a brief neurocognitive battery was administered. A significant HIV-ELS interaction was observed for amygdala volumes, which was driven by enlargements in HIV+ High-ELS participants. The HIV+ High-ELS group also demonstrated significant reductions in psychomotor/processing speed compared with HC Low-ELS. Regression analyses in the HIV+ group revealed that amygdala enlargements were associated with higher ELS, lower nadir CD4 counts, and reduced psychomotor/processing speed. Our results suggest that HIV infection and high ELS interact to increase amygdala volume, which is associated with neurocognitive dysfunction in HIV+ patients. These findings highlight the lasting neuropathological influence of ELS and suggest that high ELS may be a significant risk factor for neurocognitive impairment in HIV-infected individuals.

HIV Type 1 Viral Encephalitis After Development of Viral Resistance to Plasma Suppressive Antiretroviral Therapy

HIV-1 viral encephalitis produced by antiretroviral-resistant strains in cerebrospinal fluid (CSF), despite suppression of plasma HIV-1 RNA, has been rarely described. We report two cases of symptomatic viral encephalitis demonstrated by clinical, magnetic resonance imaging (MRI), and an inflammatory CSF profile. Viral load in CSF was 24,000 and 6850 copies/ml, whereas plasma HIV RNA level was undetectable since the beginning of therapy. A resistance test in CSF showed genotypic mutations confering resistance to the drugs the patients received for more than 2 years. In the two cases, a high baseline HIV RNA level, a low nadir CD4(+) count, and suboptimal CSF levels of atazanavir were considered as the risk factors for developing encephalitis. The two cases did not resolve with a change to antiretroviral drugs with better CNS penetration, but they had complete clinical and MRI recovery after changing to therapy considering both CNS viral resistance and penetration.

Characteristics of non‐AIDS‐defining malignancies in the HAART era: a clinico‐epidemiological study

BackgroundNon-AIDS-defining malignancies (NADM) are becoming a major cause of mortality in the era of highly active antiretroviral therapy. We wished to investigate the incidence, risks factors and outcome of NADM in an urban cohort.MethodsWe carried out an observational cohort of HIV patients with 12,746 patient-years of follow up between January 2002 and March 2009. Socio-demographics and clinical characteristics of patients diagnosed with NADM were retrospectively compared with the rest of the cohort. Causes of death and risk factors associated with NADM were assessed using logistic regression. Survival analyses were performed with Kaplan-Meier estimates. Cancer incidences were compared with those of the general population of the Brussels-Capital Region using the standardized incidence ratio (SIR).ResultsForty-five NADM were diagnosed. At inclusion in the study, patients with NADM were older than patients without NADM (47 years vs. 38 years, p < 0.001), had a longer history of HIV infection (59 months vs. 39 months, p = 0.0174), a lower nadir CD4 count (110 cells/mm3 vs. 224 cells/mm3, p < 0.0001) and a higher rate of previous AIDS events (33% vs. 20%, p = 0.0455) and of hepatitis C virus co-infection (22.2% vs. 10%, p = 0.0149). In multivariate analysis, age over 45 at baseline (OR 3.25; 95% CI 1.70-6.22) and a nadir CD4 count of less than 200 cells/mm3 (OR 3.10; 95% CI 1.40-6.87) were associated with NADM. NADM were independently associated with higher mortality in the cohort (OR 14.79; 95% CI 6.95-31.49). Women with cancer, the majority of whom were of sub-Saharan African origin, had poorer survival compared with men. The SIR for both sexes were higher than expected for Hodgkin's lymphoma (17.78; 95% CI 6.49-38.71), liver cancers (8.73; 95% CI 2.35-22.34), anal cancers (22.67; 95% CI 8.28-49.34) and bladder cancers (3.79; 95% CI 1.02-9.70). The SIR for breast cancer was lower in women (SIR 0.29; 95% CI 0.06-0.85).ConclusionsAge over 45 and a nadir CD4 count of less than 200 cells/mm3 were predictive of NADM in our cohort. Mortality was high, especially in sub-Saharan African women. Cancers with increased incidences were Hodgkin's lymphoma and anal, bladder and liver cancers in both sexes; women had a lower incidence of breast cancer.