Riccardo Raiteri

High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS.

ObjectiveTo determine the serum levels of the soluble form of the CD30 (sCD30) activation molecule in the early phase of HIV-1 infection, and to investigate the possible correlation with evolution to AIDS. MethodssCD30 values were determined by an enzyme-linked immunosorbent assay (ELISA) on serum samples collected at the time of the first evidence of HIV-1 infection in 110 individuals with a median follow-up of 56 months (range, 12–88 months), at the A1 (74 cases) or A2 (36 cases) stages of the 1993 revised Centers for Disease Control and Prevention classification. The data were evaluated using established clinical and immunological parameters, including circulating CD4+ T-cell count. The controls were 110 blood donors and 51 HIV-1 -negative subjects belonging to groups at risk for HIV-1 infection. ResultsElevated sCD30 levels ( 20 U/ml) were found in 83.6% of HIV-1 -infected cases and in 47% of at-risk seronegatives. Data analysis revealed that HIV-1-infected patients with higher sCD30 levels (>35 U/ml) experienced faster disease progression (P = 0.0002). This was also the case in patients at the earliest stage (A1) of HIV infection (P = 0.0027). In these latter cases the predictive value of sCD30 was independent of the initial absolute number of circulating CD4+lymphocytes. ConclusionsSerum levels of sCD30 are increased in the large majority of patients in the early phase of HIV-1 infection and represent an indicator of progression to AIDS independent of other prognostic parameters.

Cytokine network and acute primary HIV-1 infection.

Objective:To investigate the relationship between cytokine serum levels, peripheral blood lymphocyte subsets and clinical picture in acute primary HIV-1 infection. Patients and methods:Absolute number/μl total lymphocytes, CD4+, CD8+ and natural killer (NK) cells, as well as serum levels of soluble CD8 receptor, interleukin (IL)-1β, IL-2, lL-4, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, β2-microglobulin and 5′-neopterin were determined in 15 patients with acute primary HIV-1 infection, 16 asymptomatic HIV-1-seropositive individuals and 18 HIV-1-seronegative individuals at risk for HIV-1 infection. Results:Acute primary HIV-1 infection was characterized by significant CD4+ lymphocytopenia with low IL-2 serum concentrations, and by high absolute number of circulating CD8+ and NK cells, with elevated serum levels of soluble CD8 receptor, IL-1β, IFN-γ and 5′-neopterin. Follow-up of acute seroconverters showed a significant decrease in NK cell counts and 1L-1β levels, with an increase of IL-6. Conclusions:In acute primary HIV-1 infection, significant alteration of cytokine release, possibly induced by viral antigens, could be responsible for both clinical picture and activation of cytotoxic cells through abnormal mechanisms.

Coinfection and Superinfection of Hepatitis B Virus in Patients Infected with Human Immunodeficiency Virus: No Evidence of Faster Progression to AIDS

The influence of hepatitis B virus (HBV) on the natural history of human immunodeficiency virus (HIV) infection was evaluated in a prospective study of 347 HIV-positive, AIDS-free individuals infected through injecting drug use and sex and with known seroconversion dates. End points were CD4+ cell count < 200 x 10(6) cell/L and AIDS diagnosis. At entry, 229 had seromarkers to HBV; during the study, 107 had a CD4+ cell count < 200 x 10(6) cells/L and 66 developed AIDS. HBsAg chronic carriers, HBV infection-free subjects and those with baseline evidence of prior HBV infection did not differ in rates of progression to end points. Sexual transmission of HIV was significant predictor of CD4+ cell decline to < 200 x 10(6) cells/l [Hazard ratio (HZ): 1.56, 95% confidence interval (CI): 1.06-2.29, p = 0.0232] and progression to AIDS (HZ: 1.91, CI: 1.17-3.11, p = 0.0091). 15 HIV-positive and HBV infection-free patients had HBV seroconversion. They did not differ from those who remained HBV infection-free in rates of progression to end points, but 40% of them became HBsAg chronic carriers. These results suggest that HBV has no influence on progression of HIV disease, but that patients who have HIV before their HBV infection are more likely to become HBsAg chronic carriers than those who are infected with HBV before HIV.

Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics.

Lopinavir/ritonavir was administered to 35 HIV-infected patients after therapeutic failure with other protease inhibitors. The pharmacokinetics (trough concentrations) and baseline viral genotype were determined, together with the immunovirological outcome. The 22 responders had significantly higher mean lopinavir concentrations and lower baseline numbers of mutations. On multivariate analysis, a lopinavir concentration of 5.7 microg/ml or greater was an independent predictor of viral suppression over a 9-month follow-up period.

Longitudinal analysis of serum chemokine levels in the course of HIV-1 infection.

OBJECTIVES To investigate the correlation between the serum levels of the CC-chemokines RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and the progression of HIV-1 disease. DESIGN Retrospective analysis of serial serum samples from HIV-1 seroconverters selected according to clinical outcome. METHODS Twenty-one patients, derived from a cohort recruited between 1985 and 1996 for a prospective study of the natural history of HIV infection, were analysed. All patients had at least one HIV-1-seronegative sample within 1 year prior to the first seropositive test and were followed longitudinally throughout the course of HIV-1 infection (mean follow-up, 73.5 months). Nine were rapid progressors (RP; patients who developed AIDS within 60 months of antibody seroconversion), seven were slow progressors (SP; patients who developed AIDS after 60 months), and five were long-term asymptomatic (LTA; patients with circulating CD4+ cells higher than 400 x 10(6)/l, no signs of HIV disease, no antiretroviral therapy for more than 96 months). A total of 339 serum samples was studied (mean, 16.1 per patient). The levels of RANTES, MIP-1alpha and MIP-1beta were measured by enzyme-linked immunosorbent assay and correlated with different immunological and clinical parameters. RESULTS Over the entire follow-up period, the geometric mean of serum RANTES was significantly higher in RP [68.6 ng/ml; 95% confidence interval (CI), 56.9-82.7] than in SP (23.7 ng/ml; 95% CI, 20.0-28.2; P < 0.001) and LTA (19.5 ng/ml; 95% CI, 15.5-24.5; P < 0.001). This difference was already significant during the early clinical stages, when patients had peripheral blood CD4+ cell counts still greater than 400 x 10(6)/l (P < 0.001). By contrast, the mean serum levels of MIP-1alpha and MIP-1beta did not differ significantly between the three study groups. Multivariate analysis using the Cox proportional hazard model demonstrated that the mean serum concentration of RANTES before the development of AIDS was independently associated with the time to AIDS (relative risk, 4.5; 95% CI, 1.1-18.2; P = 0.035). In patients with low versus high mean serum RANTES before the fall of CD4+ cells below 400 x 10(6)/l, the median AIDS-free time was 117.5 and 42.7 months, respectively (P = 0.037). CONCLUSION These data suggest that an elevation of serum RANTES predicts a rapid progression of the disease since the early stages of HIV-1 infection.

The Relationship between Nevirapine Plasma Concentrations and Abnormal Liver Function Tests

Abnormal liver function tests are frequently observed in HIV-infected individuals receiving nevirapine (NVP). Here we investigate the relationship between total and unbound plasma concentrations of NVP and the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transferase (gammaGT). HIV-infected individuals [n = 85, 22 female, 34 hepatitis C or B virus (HCV or HBV(+))] receiving NVP (200 mg bd; median duration 66 weeks, range 3-189) and two nucleoside reverse transcriptase inhibitors (NRTIs) were enrolled into this study. Blood samples were taken at C(trough) (12 hr postdose) for measurement of NVP and liver function tests (ALT and gammaGT). Plasma protein bound and unbound drug was separated using ultrafiltration and NVP concentrations quantified using HPLC-MS/MS. A linear relationship was observed between total and unbound NVP C(trough) (r(2) = 0.77, p < 0.0001). Patients with elevated ALT (>37 IU/liter; n = 31) had higher NVP unbound C(trough) than those with ALT within the normal range (median 2268 vs. 1694 ng/ml, p = 0.04) but there was no difference in total C(trough). Logistic regression revealed no association between higher NVP C(trough) and ALT elevations. Significantly higher NVP total and unbound C(trough) were observed in patients with increased gammaGT (>40 IU/liter; n = 63; total 6747 vs. 4530 ng/ml, p = 0.001; unbound 2113 vs. 1557 ng/ml, p = 0.03). Significantly higher unbound NVP C(trough) was observed in HCV/HBV(+) (median 2275 vs. 1726 ng/ml, p = 0.02) and on bivariate analysis, higher NVP C(trough) was associated with HCV/HBV coinfection (chi(2) = 4.228; p = 0.04). Overall we found no strong association between NVP concentrations and hepatotoxicity. Although in this study NVP was well tolerated in HCV/HBV coinfected patients, higher plasma concentrations were observed.

High serum level of soluble CD30 in acute primary HIV-1 infection

CD30 has been suggested to play a role in HIV infection. In this study the serum concentration of soluble CD30 (sCD30) was determined by an ELISA essay on samples collected from patients with acute primary HIV‐1 infection during the acute phase (n = 17) and after seroconversion (n = 13). sCD30 during acute infection was consistently elevated (137.58 ± 120.33 versus 6.4 ± 5.4 U/ml (mean ± s.d.) in normal controls; P < 0.0001) and decreased after seroconversion (49.1 ± 66.17 U/ml; P = 0.0018 compared with acute infection). This trend mirrored the disappearance of detectable levels of HIV antigen in the blood, resulting in a direct correlation between sCD30 and HIVAg values (P = 0.002). These data suggest that the high levels of sCD30 observed during the peak concentration of HIVAg in acute primary HIV infection might reflect the high rate of viral replication.

Nevirapine Plasma Exposure Affects both Durability of Viral Suppression and Selection of Nevirapine Primary Resistance Mutations in a Clinical Setting

ABSTRACT The relationship between nevirapine plasma concentrations and the durability of both viral suppression (VS) and selection of nevirapine primary resistance mutations (PRMs) was evaluated. A nevirapine trough concentration (Ctrough) of >4,300 ng/ml was found to predict longer VS. Patients with nevirapine Ctroughs ranging from 3,100 to 4,300 ng/ml had higher probabilities of developing PRMs than those with nevirapine Ctroughs below and above this concentration interval.

Twelve-Week Treatment of Acute Hepatitis C Virus with Pegylated Interferon-α-2b in Injection Drug Users

Injection drug use is the leading risk factor for infection with hepatitis C virus, and interferon (IFN) treatment in this context is associated with a poor rate of adherence. In this article, we review our experience with injection drug users with acute hepatitis C who are treated with pegylated IFN- alpha -2b for 12 weeks. Acute hepatitis C was diagnosed according to standardized criteria, and patients were treated with a median dosage of IFN- alpha -2b of 1.33 microg/kg per week. A sustained virological response was achieved in 17 (74%) of 23 patients. A sustained virological response was achieved in 14 (87%) of 16 patients treated with a dosage of >or=1.33 microg/kg per week and in 3 (43%) of 7 patients treated with a lower dosage. Sustained virological response was significantly associated only with a pegylated IFN- alpha -2b dosage >or=1.33 microg/kg per week (P=.022). A 12-week regimen of pegylated IFN to treat injection drug users with hepatitis C has a compliance that is much higher than that reported with a 24-week regimen. Adverse effects are minimal if patients are carefully selected.

The Influence of Cytomegalovirus on the Natural History of HIV Infection: Evidence of rapid course of HIV infection in HIV-positive patients infected with Cytomegalovirus

We studied a cohort of 299 HIV-positive individuals with known date of seroconversion to evaluate the role of Cytomegalovirus (CMV) in the natural history of HIV. The study population consisted of 236 initially CMV-positive patients, 55 CMV-negative subjects and 8 CMV seroconverters. The study endpoints were the decline to CD4+ < 200 x 10(6) cells/l, AIDS, and death. The cumulative risk of CMV disease and the survival after CMV disease were also investigated. At intake, there was no inter-group difference in sex, age, risk behaviours, history of hairy leucoplakia or herpes zoster and antiretroviral treatment. During the follow-up, 108 patients fell below 200 CD4+ x 10(6) cells/l, 72 developed AIDS and 63 died. Twenty-one subjects had CMV disease. The cumulative incidence of CMV disease in the cohort was 18.9%, and 23.3% within 8 and 9 years for the initially CMV-positive patients and 33.3% and 66.7% for the CMV seroconverters (log-rank test: p = 0.101). The median survival after CMV disease was 153 days (range: 28-855, interquartile range: 261), with a cumulative survival of 45.1%, 16.9% and 4.3% within 6, 12 and 18 months, respectively. On Coxs regression, the acute HIV seroconversion was an independent predictor of each endpoint, history of hairy leucoplakia or herpes zoster being associated only with CD4+ cell decline. Baseline CMV seropositivity was related to short survival (p = 0.037) and 2 x 2 inter-group comparison showed that older individuals with sexually acquired HIV who seroconverted to CMV had higher rates of progression to the study endpoints. Our data suggest that CMV infection influences the natural history of HIV disease and that CMV disease strongly affects the survival of the HIV-positive patients.