Factors associated with long-term CD4 cell recovery in HIV-infected patients on successful antiretroviral therapy.

OBJECTIVES: The aim of the study was to study the factors associated with immunological recovery in HIV-infected patients with suppressed viral load. METHODS: Nadir and current CD4 cell counts were recorded in 821 patients, as well as many demographic, epidemiological, lifestyle, clinical, therapeutic, genetic, laboratory, liver fibrosis and viral hepatitis parameters. RESULTS: The median age of the patients was 44.4 years [interquartile range (IQR) 40.3-48.0 years], the median time since HIV diagnosis was 15.3 years (IQR 10.5-18.9 years), the median time of suppressed viral load was 7.0 years (IQR 4.0-10.0 years) and the median time on the current antiretroviral regimen was 2.8 years (IQR 1.4-4.7 years). The median nadir and current CD4 counts were 193.0 (IQR 84.0-301.0) and 522.0 (IQR 361.0-760) cells/µL, respectively, separated by a median period of 10.2 years (IQR 5.9-12.9 years). The median CD4 count gain during follow-up was 317.0 (IQR 173.0-508.0) cells/µL. Many variables were associated with CD4 cell gains in univariate analyses, including age, gender, epidemiology, prior clinical conditions, fibrosis stage, transient elastometry, aspartate aminotransferase (AST), nadir CD4 count and hepatitis B and C virus infections and genotypes, as well as the durations of follow-up since nadir CD4 count, overall antiretroviral treatment, current antiretroviral regimen, protease inhibitor therapy and suppression of viral load. Multivariate analysis revealed that longer duration of HIV suppression (P < 0.0001), more advanced clinical Centers for Disease Control and Prevention (CDC) stages (P < 0.0001), younger age (P = 0.0003), hepatitis C virus genotypes 1 and 4 (P = 0.003), sexual acquisition of HIV (P = 0.004), and lower transient elastometry values (P = 0.03) were independent predictors of CD4 cell gains. Overall, the model accounted for 14.2% of the variability in CD4 count. CONCLUSIONS: In addition to the duration of HIV suppression, HIV-related diseases, HIV epidemiology, age, hepatitis C virus genotypes, and liver fibrosis were independently associated with long-term immunological recovery.

The effect of gender and genetic polymorphisms on matrix metalloprotease (MMP) and tissue inhibitor (TIMP) plasma levels in different infectious and non-infectious conditions.

Matrix metalloproteases (MMPs) are increased in different infections due to their role in controlling immune responses and are regulated by tissue inhibitors (TIMPs). Different MMP promoter single nucleotide polymorphisms (SNPs) induce changes in MMP genes, mRNA and protein expression. Gender might also modify MMP plasma levels. In order to determine the weight of these variables on MMP secretion we studied MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4 plasma levels in 90 patients with severe bacterial sepsis, 102 with anti-retroviral (ARV)-treated HIV monoinfection, 111 with ARV-treated HIV-hepatitis C virus (HCV) co-infection and 86 non-infected controls (45 stroke and 41 trauma patients). MMP-1(-1607 1G/2G), MMP-3(-1612 5A/6A), MMP-8(-799C/T), MMP-9(-1562 C/T) and MMP-13(-77A/G) SNPs were genotyped. MMP-3 plasma levels were significantly higher in men than in women in each diagnostic group, and MMP-3 SNP allele 6A carriers also had higher levels than allele 5A carriers, an effect that was magnified by sepsis. Independent predictors of higher MMP-3 levels were male gender (P = 0.0001), MMP-3(-1612 5A/6A) SNP (P = 0.001), higher levels of TIMP-4 (P = 0.004) and MMP-8 (P = 0.006) and lower levels of MMP-1 (P = 0.03) by multivariate analysis. No strong associations with gender or SNPs were observed for other MMPs or TIMPs. In conclusion, male gender and MMP-3(-1612 5A/6A) 6A allele carriage increased MMP-3 plasma levels significantly, especially in patients with severe bacterial sepsis. This confounding gender effect needs to be addressed when evaluating MMP-3 plasma levels in any infectious or non-infectious condition.

HIV/antiretroviral therapy-related lipodystrophy syndrome (HALS) is associated with higher RBP4 and lower omentin in plasma.

Very little information is available on the involvement of newly characterized adipokines in human immunodeficiency virus (HIV)/antiretroviral therapy (ART)-associated lipodystrophy syndrome (HALS). Our aim was to determine whether apelin, apelin receptor, omentin, RBP4, vaspin and visfatin genetic variants and plasma levels are associated with HALS. We performed a cross-sectional multicentre study that involved 558 HIV type 1-infected patients treated with a stable highly active ART regimen, 240 of which had overt HALS and 318 who did not have HALS. Epidemiologic and clinical variables were determined. Polymorphisms in the apelin, omentin, RBP4, vaspin and visfatin genes were assessed by genotyping. Plasma apelin, apelin receptor, omentin, RBP4, vaspin and visfatin levels were determined by enzyme-linked immunosorbent assay in 163 patients (81 with HALS and 82 without HALS) from whom stored plasma samples were available. Student's t test, one-way ANOVA, chi-square test, Pearson and Spearman correlations and linear regression analysis were used for statistical analyses. There were no associations between the different polymorphisms assessed and the HALS phenotype. Circulating RBP4 was significantly higher (p < 0.001) and plasma omentin was significantly lower (p 0.001) in patients with HALS compared to those without HALS; differences in plasma levels of the remaining adipokines were nonsignificant between groups. Circulating RBP4 concentration was predicted independently by the presence of HALS. Apelin and apelin receptor levels were independently predicted by body mass index. Visfatin concentration was predicted independently by the presence of acquired immunodeficiency syndrome. HALS is associated with higher RBP4 and lower omentin in plasma. These two adipokines, particularly RBP4, may be a link between HIV/ART and fat redistribution syndromes.

Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients.

The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV- hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV-infected patients were studied, 111 of whom had HCV-coinfection and 68 were HCV-monoinfected. Patients with ethanol consumption >50 g/day, hepatitis B coinfection, non-infective liver diseases or HAART adherence <75% were excluded. LF was assessed by transient elastometry (TE, Fibroscan). Serum levels of MMPs (MMP -1,-2,-3,-8,-9,-10 and -13) and their tissue inhibitors (TIMP-1,-2 and -4) were measured by ELISA microarrays. Associations with LF were statistically analysed. Protease inhibitors, usually administered to patients with advanced LF were excluded from the analysis. Increased LF was significantly associated with d4T (P = 0.006) and didanosine (ddI) use (P = 0.007), months on d4T (P = 0.001) and on ARV (P = 0.025), duration of HIV (P < 0.0001) and HCV infections (P < 0.0001), higher HIV (P = 0.03) and HCV loads (P < 0.0001), presence of lipodystrophy (P = 0.02), male gender (P = 0.02), older age (P = 0.04), low nadir (P = 0.02) and current CD4(+) T-cells (P < 0.0001), low gain of CD4(+) T-cells after HAART (P = 0.01) and higher MMP-2 (P = 0.02) and TIMP-2 serum levels (P = 0.02). By logistic regression the only variables significantly associated with increased LF were: use of ddI (OR 8.77, 95% CI: 2.36-32.26; P = 0.005), male gender (OR 7.75, 95% CI: 2.33-25.64, P = 0.0008), HCV viral load (in log) (OR 3.53, 95% CI: 2.16-5.77; P < 0.0001) and age (in years) (OR 1.21, 95% CI: 1.09-1.34, P = 0.0003). We conclude that only higher HCV viral load, older age, male gender, and use of ddI associated independently with increased LF in our study.

The IL-1ß (+3953 T/C) gene polymorphism associates to symptomatic lumbar disc herniation.

PURPOSE: To determine whether polymorphisms (SNPs) in the genes encoding cytokines and nitric oxide synthase (NOS) might play some role in lumbar disc herniation (LDH). PATIENTS AND METHODS: Case-control study in which 179 patients were retrospectively reviewed. The case group was made of 50 patients with symptomatic LDH diagnosed by MRI while the control group was made of 129 individuals undergoing routine hip or knee arthroplasty with a lifetime lack of low back pain. SNPs in the cytokine genes of IL-1 [IL-1α (-889 C/T), IL-1ß (+3953 T/C)], TNF-α (-308 G/A and -238 G/A) and NOS genes [eNOS (r 27 bp, intron 4 and -786 T/C) and iNOS (22 G/A)]. RESULTS: The CC genotype and C allele of the IL-1ß (+3953 T/C) SNP were significantly more frequent among LDH patients compared to controls. On the other hand, eNOS (-768 T/C) and iNOS (22 G/A) SNPs were significantly more common in the control group. CONCLUSIONS: Carriers of the CC genotype of the IL-1ß (+3953 T/C) SNP were more frequent among LDH patients suggesting some potential role of the IL-1ß SNP on LDH pathogenesis. The eNOS (-786 T/C) and iNOS (22 G/A) SNPs were more frequent among the control subjects, suggesting their possible protective role against LDH. Genotyping these SNPs could be useful to identify persons with an increased lifetime risk of disc herniation in whom measures to avoid LDH could be implemented.

Asociación entre el polimorfismo genético de la interleucina-1Beta (3953 T/C) y la hernia discal lumbar sintomática / Association between the genetic polymorphism of interleukin-1Beta (3953 T/C) and symptomatic lumbar herniated disc

Objetivo. Evaluar la asociación entre la presencia en el genotipo de determinados polimorfismos genéticos (PG) de las citocinas y del óxido nítrico sintasa (NOS) y el desarrollo de la hernia discal lumbar (HDL) sintomática.Material y método. Se revisaron 179 pacientes en un estudio retrospectivo de casos y controles. El grupo de casos estaba formado por 50 pacientes con HDL confirmada mediante resonancia magnética. El grupo control lo componían pacientes ingresados para cirugía protésica de la cadera o de la rodilla que no presentaban ni habían presentado nunca clínica compatible con HDL. Se realizó una extracción de sangre a todos los participantes del estudio. Se genotiparon los PG de las citocinas que pretendíamos estudiar: interleucina (IL)-1 (IL-1alfa [−889 C/T] e IL-1Beta [+3953 T/C]) y factor de necrosis tumoral-alfa (TNF-alfa´ [−308 G/A] y TNF-alfa´ [−238 G/A]). Resultados. El genotipo CC y la frecuencia del alelo C del PG IL-1Beta (+3953 T/C) fueron significativamente mayores en el grupo de pacientes con HDL respecto a la población control. Por el contrario, los pacientes del grupo control portaban los PG de NOS endotelial (−768 T/C) y de NOS inducible 22 G/A con mayor frecuencia que el grupo de pacientes con HDL, esta diferencia es estadísticamente significativa para ambos polimorfismos. Conclusiones. Encontramos que ser portador del alelo C del PG IL-1Beta (+3953 T/C) puede ser un factor de predisposición para desarrollar una HDL. Por otro lado, ser portador del PG NOS endotelial (−768 T/C) y del NOS inducible 22 G/A parece comportarse como un factor protector frente al desarrollo de esta enfermedad (AU)

Objective. To evaluate the association between the presence of the genotype of certain genetic polymorphisms (GP) of the cytokine and oxide nitric synthase (NOS) and the development of lumbar herniated disc (LHD). Materials and methods. We reviewed 179 patients in a retrospective case-control study. The case group was made up of 50 patients with confirmed lumbar herniated disc diagnosed by Magnetic Resonance Imaging (MRI). The control group was made up of patients admitted for hip and knee prosthetic surgery who did not have or had not had any symptoms consistent with LHD. Blood was drawn from all of the study participants. The genotypes of the GP were obtained of the cytokines to be studied: Interleukin-1 [IL-1alpha(−889 C/T), IL-1Beta(+3953 T/C)], Tumor Necrosis Factor-alpha [TNF-alpha (−308 G/A) and (−238G/A)]. Results. The CC genotype and C allele frequency of the IL-1Betaβ PG (+3953T/C) polymorphism were significantly more frequent in patients with LDH compared to the controls. On the contrary, the control group patients carried eNos GPs (−768 T/C) and iNOS22 G/A polymorphisms more frequently than the LHD group, this difference being statistically different for both polymorphisms. Conclusions. We found that individuals who were carriers of the CC genotype of the IL-1b(+3953T/C) polymorphism showed higher susceptibility to suffer lumbar disc herniation. Furthermore, being a carrier of ENOS (−786 T/C) and iNOS (22 G/A) polymorphisms suggests that this could behave as a protection factor against disc herniation (AU)