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.

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.

The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis.

Osteomyelitis is a bone infection caused mostly by Staphylococcus aureus but also by Gram-negative bacteria. Toll-like receptors (TLRs), after recognizing microbial products, induce a signal in neutrophils, leading to NF-kappaB activation and transcription of pro-inflammatory genes. Polymorphisms in TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) genes are associated with bacterial infections, we therefore studied these polymorphisms in osteomyelitis patients. Homozygotes for the TLR4 (Asp299Gly) polymorphism were significantly more frequent among the 80 osteomyelitis patients than in the 155 healthy controls (3/80, 3.8%versus 0/155, 0%; P = 0.038). Carriers of one or two G alleles of this tlr4 polymorphism were more likely to have Gram-negative, haematogenous and/or chronic osteomyelitis than those without this mutation (P < 0.031). Patients with the TLR4 (Thr399Ile) mutant, which cosegregates with the TLR4 (Asp299Gly), were also carriers of this second polymorphism. No differences for the TLR2 (Arg753Gln) genotypes were found between patients and controls. Neutrophils of patients homozygous for the TLR4 (Asp299Gly) polymorphism showed lower LPS-induced apoptosis reduction, phosphorylation of the inhibitor of NF-kappaB, and lower IL-6 and TNF-alpha levels (P < 0.05). We report here for the first time an association between this TLR4 polymorphism and susceptibility to Gram-negative bacteria and haematogenous osteomyelitis.