José A. Carton

Sex differences in the clinical, immunological and virological parameters of HIV-infected patients treated with HAART

Objective:To compare the clinical, virological and immunological parameters of men and women at baseline and during antiretroviral treatment. Methods:Analysis over time of data collected prospectively from of 2620 patients in a large cohort of HIV-infected patients followed for 12 months after initiating a nelfinavir-based antiretroviral regimen. Results:Women had higher CD4 cell counts (P < 0.001), lower viral load (P < 0.001) and more favourable clinical profile (P < 0.001) than men at baseline. Following treatment, antiretroviral drug-naive women had higher CD4 cell count (P = 0.01) over time than drug-naive men but similar virological responses (P = 0.6); among drug-experienced individuals, women had also better immunological (P = 0.06) and similar virological (P = 0.3) responses compared with men. Consequently, the viroimmunological profile was significantly more favourable in women at each time point. The rates of clinical progression or death were also lower in women (P = 0.008), although drug toxicity was observed more commonly in women (P = 0.09). The highest viroimmunological responses were observed during the first 3 months of therapy in both sexes, although virological responses were achieved up to the 6th month in drug-naive patients. Sex was significantly associated with clinical (P = 0.01), virological (P = 0.01) and immunological (P = 0.006) responses to antiretroviral treatment in multivariate analyses after adjustment for other variables. The differences between genders were not explained by different adherence to therapy. Conclusions:Women have more favourable clinical and viroimmunological patterns than men both at baseline and during antiretroviral treatment. Sex has a small but significant influence on the clinical and laboratory outcomes of HIV infection.

IL-1β (+3954C/T) polymorphism could protect human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral treatment (HAART) against lipodystrophic syndrome

Purpose: To evaluate the impact of acquired and inherited factors on the development of lipodystrophic syndrome in patients on highly active antiretroviral therapy.Methods: Two hundred forty-three human immunodeficiency virus-infected Caucasians on highly active antiretroviral therapy were prospectively followed-up for 3 years. Eleven were naÍve and 232 were on antiretrovirals (mean, 93.0 months ± 43.8 months). Lipodystrophic syndrome was diagnosed clinically with a lipodystrophy severity grading scale. Polymorphisms of cytokines (IL-1β, IL-6, TNF-α), TLR4, and NOS genes were genotyped.Results: Ninety (37%) patients developed lipodystrophic syndrome. The polymorphic T allele of the (+3954C/T) polymorphism of IL-1β was less frequent in patients with lipodystrophic syndrome compared with those without (17.8% vs. 27.0%, P = 0.03). Factors significantly associated with lipodystrophic syndrome were time on stavudine (P < 0.001), use of stavudine (P = 0.001), absence of the T allele of the (+3954C/T) IL-1β polymorphism (P = 0.02), acquired immune deficiency syndrome diagnosis (P = 0.005), nadir levels of CD4 (P = 0.003), and time on highly active antiretroviral therapy (P = 0.003). Of these factors, only the time on stavudine (hazard ratio [95% confidence intervals] 1.007 [1.001–1.013]), use of stavudine (1.678 [1.048–2.68]), and absence of the T allele of the IL-1β (+3954C/T) polymorphism (0.569 [0.347–0.931]) were significantly associated with lipodystrophic syndrome by Cox regression.Conclusions: Genotyping of the (+3954C/T) polymorphism of IL-1β could be useful in patients starting highly active antiretroviral therapy, especially in potential users of stavudine, to predict their risk of developing lipodystrophic syndrome.

Perirenal Fat Diameter Measured by Echography Could Be an Early Predictor of Lipodystrophy in HIV Type 1—Infected Patients Receiving Highly Active Antiretroviral Therapy

Echographically measured thicknesses of perirenal and subcutaneous fat, as well as serum metabolic and anthropometric parameters, were evaluated in 74 human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy (HAART), 22 of whom were HAART-naive at baseline, who were followed-up for 27 months to detect predictive factors of lipodystrophy. Perirenal fat diameter (PRFD) at baseline differed in HAART-naive and HAART-experienced patients (P<.001), and it was the best predictor of lipodystrophy changes after 12 months of follow-up in the HAART-naive patients (hazard ratio, 7.34; 95% confidence interval, 1.18-45.49; P=.032). In addition, HAART-experienced patients in whom lipodystrophy improved had thinner baseline perirenal fat than those in whom lipodystrophy did not improve (P=.04). A PRFD of >2.6 mm at baseline or >4.9 mm during receipt of HAART suggested lipodystrophy predisposition. PRFD correlated significantly with other metabolic and anthropometric parameters. Echographically measured PRFD is associated with lipodystrophy and could be used as an early predictor of this syndrome in treatment-naive patients starting HAART.

IL‐1α (− 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‐1α and β, IL‐6, TNF‐α) and OM in adults. The IL‐1α (− 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, χ2 = 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‐1β TT (+ 3953) polymorphism was also more frequent in OM patients (P = 0.014, χ2 = 5.12, OR = 5.1, 95% CI, 1.21–52.14), but IL‐1β is in linkage disequilibrium with the IL‐1α *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‐1α TT genotype. There were no associations between OM and polymorphisms of other cytokines genes. IL‐1α 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‐1α serum levels were not significantly higher in patients with the IL‐1α (− 889) polymorphism, this does not exclude a difference in production of IL‐1α by osteoclasts or other inflammatory cells at the site of infection.

Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T), and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92), and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

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%, χ2 = 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.

Differential Body Composition Effects of Protease Inhibitors Recommended for Initial Treatment of HIV Infection: A Randomized Clinical Trial

BACKGROUND It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.

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.

Visceral leishmaniasis and other severe infections in an adult patient with p47-phox-deficient chronic granulomatous disease.

SummaryWe report a rare case of a male patient without known immunodeficiency consecutively diagnosed with visceral leishmaniasis, brain abscess and cavitating pneumonia in the 3rd decade of life. Chronic granulomatous disease (CGD) was diagnosed by a nitroblue tetrazolium test. A p47-phox mutation of the NADPH oxidase of the leukocytes was suspected by immunoblotting and confirmed by DNA analysis. The patient was homozygous for this mutation while his mother and sister were heterozygous asymptomatic carriers. After the CGD diagnosis the patient started a chronic prophylactic regimen with subcutaneous interferon-γ (0.05 mg/m2 of body surface/three times a week), and oral trimethoprim-sulfamethoxazole and itraconazole (both at 5 mg/kg/day) with no subsequent infections after 12 months of follow-up.

Factors associated with liver fibrosis in intravenous drug users coinfected with HIV and HCV

BACKGROUND Reliable non-invasive methods for the evaluation of liver fibrosis are desirable, and the risk factors associated with fibrosis are not fully identified. METHODS A cross-sectional study of a cohort of 805 HIV-HCV-coinfected patients with active HCV replication, most (95.2%) of whom were intravenous drug users, was conducted. Liver fibrosis was measured by transient elastometry with cutoff values of 7.2 kPa (significant fibrosis), 9.4 kPa (advanced fibrosis) and 14.0 kPa (cirrhosis), and by liver fibrosis indexes (LFI; APRI, Forns and FIB-4). Available liver biopsies were also evaluated. RESULTS The prevalences of significant fibrosis, advanced fibrosis and cirrhosis were 55.8%, 38.4% and 23.5%, respectively. A number of parameters were associated both in the univariate and multivariate analyses with each of the diverse fibrosis groups; however, only six of them were predictive of all stages of fibrosis: heavy alcohol intake (odds ratio [OR] 3.37, 95% confidence interval [CI] 2.02-5.59; P < 0.001), duration of HCV infection (OR 1.13, 95% CI 1.07-1.19; P < 0.001), CDC category C3 (OR 1.80, 95% CI 1.07-3.02; P=0.026), anti-HCV treatment failure (OR 4.37, 95% CI 2.24-8.55; P < 0.001), thrombocytopaenia (OR 1.015, 95% CI 1.011-1.019; P < 0.001) and increased aspartate aminotransferase (1.006, 95% CI 1.0021-1.010; P = 0.004). Furthermore, 53%, 68% and 80% of patients with significant fibrosis, advanced fibrosis and cirrhosis, respectively, had increased measures on at least one of the LFI, with the Forns index being the most sensitive. Area under the receiver operating characteristic curves of elastometry to predict histological fibrosis was 0.83 (95% CI 0.76-0.90), 0.89 (95% CI 0.83-0.95) and 0.87 (95% CI 0.80-0.94) for Metavir score ≥ F2, ≥ F3 and F4, respectively. CONCLUSIONS Elastometry constitutes a useful tool in the diagnosis and follow-up of HIV-HCV-coinfected patients. Fibrosis is associated with diverse factors, some of them treatable or preventable, which need to be addressed considering the high prevalence and course of fibrosis in these patients.