Victor Asensi

Incidence and Predictors of Severe Liver Fibrosis in Human Immunodeficiency Virus—Infected Patients with Chronic Hepatitis C: A European Collaborative Study

A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%, F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08-4.18), alcohol consumption of >50 g/day (OR, 1.61; 95% CI, 1.1-2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03-1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15% of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary, severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this population, for whom anti-HCV therapy should be considered a priority.

Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C

OBJECTIVES:Chronic hepatitis C is frequently seen in HIV-positive subjects infected through needle sharing or transfusion of contaminated blood products. Progression to end-stage liver disease seems to occur faster in these patients. As the life expectancy of HIV-infected persons has dramatically improved since the introduction of highly active antiretroviral therapies, cirrhosis and eventually hepatocellular carcinoma (HCC) may be recognized at an increasing rate in patients coinfected with HIV and hepatitis C virus (HCV).METHODS:We identified the main features of HIV-infected individuals with end-stage liver disease due to HCV infection and diagnosed with HCC in three HIV/AIDS referral centers, and compared these features to those of a control group of patients with HCV-related HCC but without HIV infection.RESULTS:Seven HIV-infected patients were identified. Of these, six were <45 yr of age and had been intravenous drug users. The mean time between exposure to HCV and the development of HCC was estimated to be 17.8 yr. Two subjects were coinfected with hepatitis B and delta viruses, respectively. Only one individual had been diagnosed of an AIDS-defining condition before the diagnosis of HCC was made. However, all subjects had <500 CD4+ T cells at the time of HCC diagnosis. Five died within the first 4 months of follow-up. Patients in the control group (n = 31) were significantly older (68.9 ± 8.9 vs 42.2 ± 10.4; p < 0.001) and the duration of HCV infection was significantly longer (28.1 ± 10.9 vs 17.8 ± 2.7; p < 0.05) than in those with HIV-HCV coinfection.CONCLUSIONS:HCC seems to occur at a younger age and after a shorter period of HCV infection in subjects coinfected with HIV. Thus, treatment of CHC should be encouraged in HIV-positive patients, and in those with HCV-related cirrhosis the periodic monitoring of α-fetoprotein and abdominal ultrasonography should be recommended.

Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.

Objective: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals. The aim of the study was to compare the main features of HCC in HIV-seropositive individuals with those in to HIV-negative patients. Patients and methods: All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study as cases. HCC cases that occurred in the province of Brescia, North Italy, in the period 1995–1998 and all cases reported at the Italian Liver Cancer Project were enrolled as controls. All data were collected using a standardized case report form. The main clinical and epidemiological characteristics of patients with HCC and their survival were compared between HIV-positive and uninfected subjects. Results: Forty-one HIV-infected subjects with HCC were identified. Multivariate analysis adjusted for age and sex identified an association between HIV infection and HCV infection [odds ratio (OR), 11; P = 0.005], and infiltrating tumours and/or extranodal metastasis at presentation (OR = 11.8; P < 0.001). HIV infection was independently associated with shorter survival (hazard ratio, 1.63; P = 0.015). Conclusions: HCC in HIV-infected patients is mainly associated with underlying chronic hepatitis C and has a more aggressive clinical course. Thus, preventative strategies (including the treatment of hepatitis C) should be implemented in the management of HIV/HCV-coinfected patients.

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.

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‐κB 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‐κB, and lower IL‐6 and TNF‐α 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.

Cd8dim and Nkg2d Expression Defines Related Subsets of Cd4+ T cells in Hiv-infected Patients With Worse Prognostic Factors

The past several years have seen substantial developments in the use of alternative specimens for drug analysis. The use of oral fluid has been found to offer significant promise when detection of relatively recent use of drugs is sought in a relatively noninvasive manner. Although there are a number of factors that affect drug concentration in oral fluid, there appears to be a reasonable correlation between blood and oral fluid concentrations of drugs. Collection techniques can artificially affect production of oral fluid and its subsequent pH. These need to be understood, as does local absorption of drug, in situations where drug may be present in the oral cavity (eg, smoking or sublingual absorption). Nevertheless, it is essential that devices used to collect oral fluid are checked to ensure reasonable stability and recovery of absorbed drug. The most common applications include workplace testing for drugs of abuse, particularly post-incident, and roadside detection of illicit drugs. Therapeutic drug monitoring has been shown to be useful for a number of drugs that have traditionally been measured in plasma/serum.CD4+ T lymphocytes expressing CD8dim (DP: CD4+ CD8dim) or NKG2D represent cytotoxic effector populations, which have been involved in viral infections and chronic diseases. The frequency of DP cells was analyzed by flow cytometry in 300 consecutive HIV-infected patients and 50 healthy controls. NKG2D expression and memory/effector markers in CD4+ T cells were also studied, in addition to virologic and genetic factors involved in DP T-cell expansion. HIV-infected patients showed a significantly higher frequency of DP cells than controls, mainly in patients with advanced disease. Expansion of DP cells was related to NKG2D appearance in CD4+ T cells and was predicted by CD4+ CD28null T-cell levels. Cells expressing CD8dim and NKG2D+ cells are closely related populations with a similar pattern of surface markers, perforin expression, and responses to activation. We also found that these subsets seem to share an ontogenic relationship and TcR oligoclonality. In this way, cytomegalovirus infection and certain HLA alleles, such as DR7, conditioned the expansion of DP cells. Their common ontogenic origin and oligoclonality, possibly due to repeated encounters with the same antigen, could result in a limitation of the repertoire of responder cells and in a worse prognosis 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.

Didanosine, Lamivudine, and Efavirenz versus Zidovudine, Lamivudine, and Efavirenz for the Initial Treatment of HIV Type 1 Infection : Final Analysis (48 Weeks) of a Prospective, Randomized, Noninferiority Clinical Trial, GESIDA 3903

BACKGROUND The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. METHODS We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis. RESULTS Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003). CONCLUSIONS At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity. CLINICAL TRIALS REGISTRATION NCT00256828.

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.