The influence of the patients' educational levels on socioeconomic, clinical, immunological and virological endpoints.

To analyse the influence of educational levels on diverse baseline and follow-up characteristics and outcomes of HIV-infected patients, we sequentially evaluated 1352 individuals with known educational levels, who initiated a nelfinavir-based regimen. Higher educational degrees were associated with better baseline clinical (P=0.03) and immunological (P=0.003) conditions, not related to transmission categories, which were also observed during follow-up (P=0.003). However, these differences were only found in antiretroviral-experienced patients (P=0.002), while naive patients had very similar values (P=0.8). Overall, there were different CD4 responses (P=0.06), but not viral load responses (P=0.6), to antiretroviral therapy according to the educational level, but these differences were more marked in the last six months of follow-up (P=0.008). Patients with higher educational degrees had higher rates of adherence to medical appointments both before (P=0.0003) and during the study period (P=0.01), as well as to antiretroviral therapy in univariate (P=0.003) and multivariate analyses (P=0.007). Similarly, baseline CD4 counts proved to be independently associated with education after adjustment for other variables (P=0.0006). The educational groups also differed in diverse socioeconomic parameters and certain beliefs about HIV infection (P<0.0001 for each). We conclude that the patient's educational level influences clinical and immunological outcomes of HIV infection. This impact is probably mediated through differences in the long-term effects of treatment, as a result of adherence to antiretroviral therapy and to medical indications. The evaluation of social aspects such as the patient's education should be incorporated into routine clinical practice to improve the results of treatment.

A fatal case of Babesia divergens infection in Northwestern Spain.

We describe a fatal case caused by the intra-erythrocytic Babesia divergens parasite in an elderly woman. This is the third case of fatal babesiosis reported in the last 15 years in Europe, and the only one in a patient with an intact spleen.

Factors associated with poor immunologic responses despite viral suppression in markedly immunosuppressed patients.

To determine the factors associated with poor immunologic responses despite viral suppression in markedly immunocompromised patients (

Course of liver fibrosis in HIV-hepatitis C virus-coinfected patients depending on the response to hepatitis C therapy.

To evaluate the course of liver fibrosis, 328 HIV-hepatitis C virus (HCV)-coinfected patients (210 HCV treated and 118 HCV untreated) were followed-up for 38-42 months. Liver fibrosis was assessed by biopsy or elastometry at baseline and by elastometry afterward, in addition to other noninvasive indexes. A combined liver stiffness stage (LSS) was established and evaluated over time. Eighty patients had sustained virological response (SVR) and 130 had treatment failure (TF) after a standard course of peginterferon-ribavirin therapy. LSS decreased significantly in all fibrosis indexes during HCV therapy in treated patients, but the improvement persisted only in those with SVR. At the end of study, median elastometry values suffered variations of -29%, -5.0%, and +15.4% in SVR, TF, and untreated patients, respectively. Likewise, LSS worsened in 2.5%, 33.1%, and 39% of these groups, respectively: [OR (95% CI) 19.3 (4.4-119), p<0.001] for TF vs. SVR; [24.9 (5.6-154), p<0.001] for no therapy vs. SVR; and [1.29 (0.74-2.3), p=0.40] for no therapy vs. TF. LSS improved in 53.8%, 19.2%, and 5.9% of these groups, respectively: [4.88 (2.51-9.53), p<0.001] for SVR vs. TF; 18.4 (7.17-49.4), p<0.001 for SVR vs. no therapy; and 3.78 (1.47-10.1), p=0.003 for TF vs. no therapy. Independent predictive factors of LSS improvement or worsening were as follows: alcohol abuse [OR (95% CI) 0.48 (0.20-0.99), p=0.047] and [2.45 (1.19-5.03), p=0.016], respectively; SVR [27.7 (6.41-168), p<0.001] and [0.15 (0.07-0.31), p<0.001], respectively; and lower baseline CD4 counts [1.92 (1.08-3.45), p=0.026] and [0.31 (0.15-0.63), p=0.001], respectively. SVR was usually associated with regression of noninvasive liver fibrosis markers, whereas TF and HCV-untreated patients experienced poorer outcomes.

The effect of unsuccessful treatment with peginterferon and ribavirin on the liver fibrosis course of HIV/HCV-coinfected patients.

BACKGROUND: The course over time of different fibrosis parameters in HIV/HCV-coinfected patients who did not suppress HCV during anti-HCV therapy, and in patients who suppressed HCV but relapsed after treatment discontinuation is unclear. METHODS: A total of 248 patients were included in the study (81 non-responders, 49 relapsers, and 118 control, untreated patients). Four primary non-invasive fibrosis indices (transient elastometry, APRI, Forns, and FIB4), as well as other fibrosis parameters, were evaluated in each group at baseline, at the end of anti-HCV therapy and at the end of follow-up (median 39.35 months from baseline). RESULTS: Groups were comparable in baseline characteristics, except for lower fibrosis indices in the control group. In this group there was a consistent increase in all fibrosis indices over time. On the contrary, treated patients experienced certain improvements in these indices during the period of treatment and a further worsening when the treatment was stopped, to reach the pretreatment values at the end of follow-up. Relapsers had also more favorable course than non-responders in each fibrosis parameter, but the differences were small and not statistically significant. CONCLUSIONS: HIV/HCV-coinfected patients who undergo unsuccessful anti-HCV treatment experience some improvement in liver fibrosis as compared to untreated patients, although the differences are small. Relapsers have also a more favorable fibrosis course than non-responders, but the differences are minimal. These improvements are only limited to the treatment period. Therefore the effect of unsuccessful treatment would only represent a transitory delay in fibrosis progression.

Immunological status does not influence hepatitis c virus or liver fibrosis in HIV-hepatitis C virus-coinfected patients.

The possible effects on liver fibrosis and HCV viral load of the immunological status of HIV-HCV-coinfected patients are unclear. A cohort of HIV-HCV-coinfected patients was divided according to the current CD4 counts into poor (≤200/µl, n = 117) or good (≥500/µl, n = 441) immunological status. The groups were compared for diverse HCV- and fibrosis-related parameters. Fibrosis was evaluated by transient elastometry and other noninvasive indexes. Many variables were significantly associated with the immunological status in univariate analyses, including fibrosis parameters. However, in multivariate analyses current immunological status or nadir CD4 were not associated with HCV viral load (p = 0.8 and p = 0.3, respectively), liver fibrosis at the time of evaluation (p = 0.9 for both), or fibrosis progression over time (p = 0.98 and p = 0.8, respectively). The factors independently associated with significant fibrosis, advanced fibrosis, and cirrhosis, as compared with minimal or no fibrosis, were alcohol abuse [OR 3.57 (95% CI 1.43-8.85), p = 0.006; OR 10.10 (3.75-27.03), p < 0.0001; and OR 31.25 (10.6-90.90), p < 0.0001, respectively], HBsAg positivity [OR 9.09 (1.47-55.56), p = 0.02; OR 55.56 (9.80-333.33), p < 0.0001; and OR 43.48 (4.76-476.19), p = 0.0008, respectively], and platelet counts [OR 0.994 (0.989-0.998), p = 0.006; OR 0.990 (0.985-0.995), p = 0.0003; and OR 0.985 (0.979-0.991), p < 0.0001, respectively]. Immunological status did not associate with any fibrosis stage (significant fibrosis, p = 0.7; advanced fibrosis, p = 0.4; and cirrhosis p = 0.9). The current or past immunological status of HIV-HCV-coinfected patients does not seem to have any significant influence on HCV viral load or on the development of liver fibrosis when adjusting for important covariates.

Gender differences in liver fibrosis and hepatitis C virus-related parameters in patients coinfected with human immunodeficiency virus.

OBJECTIVES: To evaluate gender differences in liver fibrosis and hepatitis C virus-related parameters in patients coinfected with human immunodeficiency virus. METHODS: Transversal study of 782 patients who underwent a complete clinical and laboratory evaluation. Fibrosis was measured by transient elastometry (TE) and by commonly used laboratory-derived fibrosis indexes. RESULTS: Men were older, had higher rates of alcohol abuse, higher HCV viral load and liver tests, lower platelet values, poorer CDC clinical stages, longer duration of HCV infection, shorter time on successful antiretroviral therapy (ART) and had appreciably more advanced fibrosis than women. Multivariate analysis revealed that male gender (P < 0.0001), longer time since HCV acquisition (P < 0.0001), alcohol abuse (P < 0.0001), HCV genotype 3 (P=0.01), shorter time on successful ART (P=0.005) and worse CDC clinical stages (P=0.03) were independently associated with significant or higher stages of fibrosis. Male gender was also independently predictive of advanced or higher stages of fibrosis (P=0.06) or cirrhosis (P=0.02). In patients with no alcohol abuse, men had worse fibrosis parameters than women (P < 0.01 for each), but these differences decreased in patients with alcohol abuse and became non-significant. CONCLUSIONS: HIV-HCV-coinfected women have more favorable HCV virological and clinical profile than men and, particularly, lower degrees of fibrosis. Alcohol abuse seemed to result more deleterious in women than in men. The reportedly poorer outcomes of liver disease in HIV-HCV-coinfected patients, as compared with their HCV-monoinfected counterparts, could be ameliorated by addressing these cofactors, some of them preventable or treatable.

CD4 responses in the setting or suboptimal virological responses to antiretroviral therapy: features, outcomes, and associated factors.

The factors associated with discordant viroimmunological responses following antiretroviral therapy are unclear. We studied 1380 patients who initiated a protease inhibitor (PI)-based antiretroviral regimen and who fulfilled the criteria for inclusion. Of them, 255 (18.5%) had CD4 increases > or =100 cells/microl after 1 year of therapy despite detectable viral load (immunological responders); they were compared with 669 patients (48.5%) who had CD4 increases <100 cells/microl regardless of their final viral load (immunological nonresponders). Immunological responders had higher rates of sexual acquisition of HIV (p = 0.03), lower rates of clinical progression (p = 0.02), higher probabilities of being naive to antiretroviral therapy (p = 0.006) or to PI if antiretroviral experienced (p = 0.03), higher rates of receiving only nucleoside reverse transcriptase inhibitors in addition to the PI (p = 0.04), and lower baseline CD4 counts (p = 0.007) and higher viral loads (p = 0.009), as compared with nonresponders. Multivariate analysis revealed that sexual transmission of HIV (homosexual p = 0.004, heterosexual p = 0.03), no prior PI experience (p = 0.005), absence of clinical progression (p = 0.02), and lower baseline CD4 counts (p = 0.03) were independently associated with immunological response. However, these factors differed according to the patients' prior antiretroviral status, as higher baseline viral load was also associated with immunological response in antiretroviral-experienced patients (p = 0.02), whereas baseline CD4 count (p = 0.007) was the only predictive parameter in antiretroviral-naive patients. We conclude that immunological responses despite suboptimal viral suppression are common. Prior PI experience, HIV transmission category, baseline CD4 counts, and clinical progression were independently predictive of this condition, although the associated factors were different depending on the patient's prior antiretroviral history.

Bax gene G(-248)A promoter polymorphism is associated with increased lifespan of the neutrophils of patients with osteomyelitis.

BACKGROUND: Patients with osteomyelitis have a decreased rate of spontaneous apoptosis of their peripheral blood neutrophils. The G(-248)A polymorphism in the promoter region of the bax gene is associated with prolonged peripheral blood neutrophil survival in leukemic patients and may play some role in osteomyelitis. METHODS: Bax G(-248)A promoter polymorphism was detected by DNA amplification using polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Spontaneous apoptosis of peripheral blood neutrophils was measured by propidium iodide, annexin V, and flow cytometry, and Bax was quantified by Western blotting. RESULTS: The bax promoter polymorphism A allele was significantly more frequent in 80 patients with osteomyelitis than in 220 healthy donors (18.1% vs. 10.6%, chi=4.84, odds ratio=1.81, 95% confidence interval=1.06-3.07, P=.028). Carriers of the A allele had a lower apoptotic rate of their peripheral blood neutrophils compared with noncarriers (33.3+/-16.7 vs. 43.1+/-3.1, P=.036). Patients with the AA genotype showed a lower expression of the Bax protein compared with carriers of other genotypes (P=.038). CONCLUSIONS: Substitution of a nucleotide G-->A at position -248 in the bax gene was more frequent in patients with osteomyelitis and was associated with a longer lifespan of their peripheral blood neutrophils and lower Bax protein expression. These findings may play a role in the pathogenesis of osteomyelitis.

In vivo interleukin-6 protects neutrophils from apoptosis in osteomyelitis.

Polymorphonuclear neutrophils are critical for resolution of bacterial infections. In tissues, most of the neutrophils quickly die through apoptosis. Using propidium iodide DNA staining and DNA gel electrophoresis, we found that spontaneous apoptosis of neutrophils from patients suffering osteomyelitis (n = 52) was significantly decreased in relation to control neutrophils (n = 20) (40.2% +/- 25.2% versus 54.5% +/- 23.5%; P < 0.03). Incubation of neutrophils from normal volunteers with sera from patients with osteomyelitis reduced apoptosis from 79.1% +/- 14.8% in control sera to 62.2% +/- 18.7% in osteomyelitis sera. A significant increase of serum interleukin-6 (IL-6) and IL-1alpha was found in osteomyelitis (IL-6, 8.8 +/- 11.9 pg/ml versus 1.8 +/- 1.2 pg/ml in controls [P < 0.004]; IL-1alpha, 3.8 +/- 6.4 pg/ml versus 1.0 +/- 2.2 pg/ml in controls [P < 0.02]). No differences in the levels of other cytokines, such as tumor necrosis factor alpha, were found. There was an inverse correlation between IL-6 levels and neutrophil apoptosis (r = -0.855; P < 0.007), but this was not the case for other cytokines. The antiapoptotic effect of the osteomyelitis sera was reversed with anti-IL-6 antibodies (P < 0.03) and was reproduced with recombinant human IL-6 (P < 0.001). The longer life span of neutrophils in osteomyelitis induced by IL-6 could contribute to the tissue damage that occurs in these chronic bone infections.

IL-1 alpha (-889) promoter polymorphism is a risk factor for osteomyelitis.

As osteomyelitis (OM) induces the synthesis of inflammatory cytokines and IL-1 mediates bone resorption by osteoclasts we determined if there is an association between certain common polymorphisms of the genes encoding proinflammatory cytokines (IL-1 alpha and beta, IL-6, TNF-alpha) and OM in adults. The IL-1 alpha (-889) TT genotype was significantly more frequent among 52 OM patients than in 109 healthy controls (13/52, [25.0%] vs. 9/109, [8.3%], P = 0.0081, chi(2) = 7.01, OR = 3.7, 95% CI, 1.35-10.34). Patients who were homozygous for the T allele were younger than the rest of the OM patients (mean age 35.7 +/- 11.5 vs. 58.1 +/- 18.6 years, P = 0.001). IL-1 beta TT (+3953) polymorphism was also more frequent in OM patients (P = 0.014, chi(2) = 5.12, OR = 5.1, 95% CI, 1.21-52.14), but IL-1 beta is in linkage disequilibrium with the IL-1 alpha *T (P < 0.001). Route of infection, chronicity of the infection, type of microorganism isolated, and frequency of relapses were similar in patients with and without the IL-1 alpha TT genotype. There were no associations between OM and polymorphisms of other cytokines genes. IL-1 alpha serum levels were significantly increased in all the OM patients independently of their IL-1 genotype compared to the controls (P = 0.021). Although IL-1 alpha serum levels were not significantly higher in patients with the IL-1 alpha (-889) polymorphism, this does not exclude a difference in production of IL-1 alpha by osteoclasts or other inflammatory cells at the site of infection.