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A Cozzi Lepri

Publications and source records attributed to A Cozzi Lepri.

At least 19 recordsLinked to original sources
PubMed2001

Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in previously drug-naive individuals.

BACKGROUND: Relatively little is known about the long-term durability of viral suppression in individuals initially achieving a viral load of less than 50 copies/ml within 24 weeks of starting antiretroviral therapy, nor the extent to which therapy interruption accounts for the loss of suppression. METHODS: We intensely followed all 336 antiretroviral-naive patients attending the Goethe Universitat Clinic who began multi-drug combination regimens and in whom a viral load of less than 50 copies/ml was achieved within 24 weeks, in order to assess the risk of viral load rebound. Inspection of case notes allowed the distinction of viral rebound according to whether there was an associated complete interruption of therapy. RESULTS: A total of 61 patients experienced viral rebound during 543.1 person-years of follow-up, giving a 25.3% risk of rebound by 3.3 years from first achieving viral suppression. However, for 47 of the patients with viral rebound there was an associated documented complete interruption of antiretroviral therapy, mostly as a result of co-morbidities, leaving 14 who appear to represent a failure of the virological efficacy of therapy (viral breakthrough; 5.2% risk by 3.3 years). The risk of viral breakthrough declined with the increased duration of suppression (P = 0.01). CONCLUSION: The intrinsic virological effectiveness of multi-drug antiretroviral therapy in previously drug-naive individuals appears to be such that viral suppression, once achieved, can be maintained for several years in patients not interrupting therapy. The major challenge is to develop regimens that can be taken consistently and safely for such long periods of time.

Adult↗
PubMed2001

When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from the ICONA study.

OBJECTIVES: To compare the response to highly active antiretroviral therapy (HAART) in individuals starting HAART at different CD4 cell counts. DESIGN: The mean increase in CD4 cell count and rate of virological failure after commencing HAART were measured in antiretroviral-naive patients (1421) in a large, non-randomized multicentre, observational study in Italy (ICONA). Clinical endpoints were also evaluated in a subset of patients who started HAART with a very low CD4 cell count. RESULTS: After 96 weeks of therapy, the mean rise in CD4 cell count was 280, 281 and 186 x 10(6) cells/l in patients starting HAART with a CD4 cell count < 200, 201--350 and > 350 x 10(6) cells/l, respectively. Patients starting HAART with a CD4 cell count < 200 x 10(6) cells/l tended to have a higher risk of subsequent virological failure [relative hazard (RH), 1.15; 95% confidence interval (CI), 0.93--1.42] compared with patients starting with > 350 x 10(6) cells/l. There was no difference in risk between the 201--350 and the > 350 x 10(6) cells/l groups (RH, 1.0; 95% CI, 0.79--1.29). The incidence of new AIDS-defining diseases/death in patients who started HAART with a CD4 count < 50 was 0.03/person-year (95% CI, 0.10--0.33) during the time in which the patient's CD4 cell count had been raised to > 200 x 10(6) cells/l. CONCLUSIONS: There was no clear immunological or virological advantage in starting HAART at a CD4 cell count > 350 rather than at 200--350 x 10(6) cells/l. The increase in CD4 cells restored by HAART is meaningful in that they are associated with reduced risk of disease/death.

Adolescent↗
PubMed2000

Adrenaline-induced mobilization of T cells in HIV-infected patients.

The present study aimed to investigate lymphocyte mobilization from peripheral cell reservoirs in HIV-infected patients. Nine HIV-infected patients on stable highly active anti-retroviral therapy (HAART), eight treatment-naive HIV-infected patients and eight HIV- controls received a 1-h adrenaline infusion. The adrenaline infusion induced a three-fold increase in the concentration of lymphocytes in all three groups. All HIV-infected patients mobilized significantly higher numbers of CD8+ cells but less CD4+ cells. All subjects mobilized CD45RA+CD62L+ and CD8+CD28+ cells to a lesser extent than CD45RO+CD45RA- and CD8+CD28-cells. Furthermore, high numbers of CD8+CD38+ cells were mobilized only in the HIV-infected patients. It was therefore predominantly T cells with an activated phenotype which were mobilized after adrenaline stimulation. It is concluded that the HIV-associated immune defect induced an impaired ability to mobilize immune-competent cells in response to stress stimuli. Furthermore, the study does not support the idea that CD4+ T cells are trapped in lymph nodes by HIV antigens, because untreated and HAART-treated HIV-infected patients mobilized similar numbers of CD4+ T cells. Finally, no evidence was found for the existence of a HAART-induced non-circulating pool of CD4+ T cells.

ADP-ribosyl Cyclase↗
PubMed2000

Resistance profiles in patients with viral rebound on potent antiretroviral therapy.

The prevalence of phenotypic drug resistance was assessed in 60 patients with a viral rebound after they received a protease inhibitor (PI)- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen (baseline). Resistance testing was done within 36 weeks of viral rebound; no resistance testing was available at baseline. All patients had previously received zidovudine; 86.0% had received lamivudine. In total, 45.1% of the patients had strains resistant to the PI that they started and 88.9% given nevirapine had strains with reduced susceptibility to that drug. Overall, 46 patients (76.7%) harbored a strain resistant to >/=1 drug of their initial PI- or NNRTI-containing regimen. Of 53 patients who remained on treatment at the time of the study (40 had switched to a different combination from that at baseline), 6 harbored isolates susceptible to all drugs they had ever received. Thus, patients with viral rebound while on potent antiretroviral therapy usually have reduced susceptibility to >/=1 drug. Viral rebound also occurs in persons in whom resistant strains could not be detected by the assay used.

Drug Resistance↗
PubMed1999

Natural immunity and HIV disease progression.

OBJECTIVE: To investigate the clinical implications of impaired levels of the natural immunity mediated by natural killer (NK) cells and lymphokine activated killer (LAK) cells during infection with HIV-1. DESIGN: Data used were from 172 individuals with an estimated measure of NK cell activity and 146 with an estimated measure of LAK cell activity. Patients had active HIV infection at the time of enrolment in the study and have been followed-up prospectively for a median of 3.0 years. METHODS: The lytic activity of NK cells and LAK cells, the CD4 T lymphocyte count, and the concentration of CD16/CD56 NK cells were measured at enrolment. HIV RNA in plasma was measured retrospectively. Survival analysis was performed considering three main endpoints: CD4 cell counts below 100 x 10(6) cells/l, clinical AIDS, and death. RESULTS: In unadjusted analysis and after adjustment for age, CD4 T lymphocyte count and plasma HIV RNA at enrolment, low LAK cell activity was significantly associated with higher risk of progression to a CD4 T lymphocyte count < 100 x 10(6) cells/l (crude P = 0.001; adjusted P = 0.04) and to death (crude P = 0.0002; adjusted P = 0.02). Patients with low NK cell responsiveness to interferon-alpha tended to be at higher risk of death (crude P = 0.04; adjusted P = 0.13) whereas unstimulated NK cell activity and the concentration of NK cells were of no prognostic value for patients in this cohort. CONCLUSIONS: The present study suggests that low LAK cell activity and low NK cell responsiveness to interferon-alpha may be important in the pathogenesis of HIV infection.

CD4 Lymphocyte Count↗
PubMed1998

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection.

OBJECTIVE: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. DESIGN: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54). SETTING: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. MAIN OUTCOME MEASURE: Survival time. RESULTS: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). CONCLUSIONS: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

Adult↗
PubMed1998

Evaluating the effect of year of seroconversion on HIV progression in cohort studies. Italian Seroconversion Study.

OBJECTIVES: To show how a spurious association between the calendar year of seroconversion and HIV progression arises as a result of censoring the follow-up of individuals at their last visit, when the individuals' visits are intermittent. DESIGN: A notional cohort of 1140 seroconverters and a cohort study of 1270 HIV-infected individuals seroconverted between 1985 and 1994, and followed up to December 1995 (the Italian Seroconversion Study cohort). METHODS: Failure times and rate of the patients attending the clinic over the study period were simulated for the notional cohort. Three separate scenarios with different probabilities of making a visit were considered. Standard survival analysis techniques were used to assess the effect of the year of seroconversion on HIV progression. The progression to a CD4 cell count of 200 x 10(6)/l according to the calendar year of seroconversion in the Italian Seroconversion Study was assessed using different censoring strategies. RESULTS: A spurious effect of the year of seroconversion consistently appeared in 100 repeated simulations. When ignoring the visits occurring after the first year of follow-up in the Italian Seroconversion Study cohort, results supported the hypothesis of no effect of the year from seroconversion. CONCLUSIONS: The choice of the censoring strategy is crucial when assessing the effect of year of seroconversion using survival analysis in cohort studies with intermittent visit structure. Different censoring strategies should be considered before firmly concluding that more virulent strains or the use of treatment are modifying the natural history of HIV disease from cohort studies of this nature.

Cohort Studies↗
PubMed1998

A practical approach to adjusting for attrition bias in HIV clinical trials with serial marker responses.

OBJECTIVES: To illustrate a simple approach to adjusting for bias due to drop-outs (i.e., attrition bias) when evaluating the effect of a certain therapy in HIV clinical trials using the mean change in plasma viral load. To evaluate its validity and to compare its performance with that of another simple method for handling drop-outs: the last observation carried forward (LOCF) method. DESIGN: Data from a notional treated group of 100 patients followed up to 52 weeks were generated. Attrition bias was introduced by mimicking selective patient drop-out (i.e., more likely in patients doing badly). METHODS: The difference between the true mean change in HIV RNA levels at 52 weeks and the observed mean change because of drop-outs was calculated (attrition bias). The reduction in bias obtained by using the proposed approach was then calculated and compared with that obtained by using the LOCF method. To assess the performance of the methods over the entire follow-up, the mean areas under the curves were considered. RESULTS: Our method reduced the bias by a clinically relevant amount in a variety of different settings. In most of our simulations, bias was reduced by a larger amount than that obtainable from using the LOCF method. CONCLUSIONS: The current situation is that results from trials in HIV infection are invariably presented with no associated attempt to quantify the attrition bias present. Attrition-adjusted plots of mean change in HIV RNA should, we believe, be presented alongside usual plots as a form of sensitivity analysis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

The rate of CD4 decline as a determinant of progression to AIDS independent of the most recent CD4 count. The Italian Seroconversion Study.

The data of two cohort studies of HIV-infected individuals were used to examine whether the rate of CD4 decline is a determinant of HIV progression, independent of the most recent CD4 count. Time from seroconversion to clinical AIDS was the main outcome measure. Rates of CD4 decline were estimated using the ordinary least squares regression method. AIDS incidences were compared in individuals who had previously experienced either a steeper or a less steep rate of CD4 decline. Cox proportional hazards model including a time-dependent covariate for the rate of CD4 decline was performed. The rate of prior CD4 decline was significantly associated with the risk of developing AIDS independently from the most recent CD4 count, with a 2% increase in hazard of AIDS (P < 0.01) for a difference of 10 cells/mm3 in the estimated yearly drop in CD4 count. This finding gives scientific credit to the belief that individuals with a prior steeper CD4 decline consistently have a higher subsequent risk of developing AIDS than those with a less steep prior decline.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Production of beta-chemokines in human immunodeficiency virus (HIV) infection: evidence that high levels of macrophage inflammatory protein-1beta are associated with a decreased risk of HIV disease progression.

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES production were measured by ELISA in whole blood that had been stimulated for 4.5 h with phytohemagglutinin. The blood was from 90 healthy human immunodeficiency virus (HIV)-negative controls and from 245 HIV-infected subjects who were followed for < or = 4.5 years. HIV-infected persons without AIDS had increased levels of MIP-1alpha, MIP-1beta, and RANTES (P < .01) compared with levels in controls. Subjects with AIDS, compared with controls, had decreased production levels of MIP-1beta (P < .0001) and similar levels of MIP-1alpha and RANTES. A high level of MIP-1beta production was associated with a decreased risk of progressing to AIDS or death, as determined by univariate analysis (P < .01) and adjusted for CD4 cell count and age (P = .07, P = .06, respectively). The findings suggest that the production level of beta-chemokine changes during HIV infection and that a high level of beta-chemokine production in peripheral blood lymphocytes may be associated with less rapid disease progression in HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Low production of interferon gamma is related to disease progression in HIV infection: evidence from a cohort of 347 HIV-infected individuals.

A total of 347 HIV-seropositive individuals attending the Department of Infectious Diseases at Rigshospitalet in Copenhagen and 110 age- and sex-matched healthy controls not at risk for HIV infection were included in this study. Interferon gamma (IFN-gamma) production was measured in whole blood of 223 HIV-seropositive individuals (68 had developed AIDS at enrollment) and 99 healthy sex- and age-matched controls 4.5 hr after challenge with phytohemagglutinin. HIV-infected individuals for whom IFN-gamma production was measured were followed with a median follow-up time of 2.89 years (range, 0.02-4.54 years) from the date of enrollment. Survival analysis was performed considering three different end points: (1) a CD4 count below 100 cells/mm3, (2) an AIDS diagnosis defined according to the 1993 Centers for Disease Control definition, and (3) death. The production of IFN-gamma was highly increased in the blood of HIV-infected individuals without AIDS, but decreased in the blood of AIDS patients (both compared to controls). In the HIV-infected individuals, the total production of IFN-gamma was positively correlated with the number of CD8+ T lymphocytes and with the number of CD16+/CD56+ natural killer cells and negatively correlated with serum levels of beta2-microglobulin. Low levels of IFN-gamma production were associated with an increased risk of experiencing a CD4 count below 100 cells/m3 and death, analyzed in both univariate analysis and in multivariate analysis adjusting for CD4 counts and age. Thus, changes in production of IFN-gamma seem to be truly related to the risk for disease progression in HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Cross-sectional studies in AIDS pathogenesis: how far can they mislead us?

When investigating variables thought to be of potential importance to AIDS pathogenesis, it is common practice to initially carry out a cross-sectional study comparing those with symptomatic disease/low CD4 counts with those with no symptoms/high CD4 counts. While it is widely appreciated that such studies have weaknesses compared with those involving patient follow-up, the particular biases likely to arise in the context of HIV infection have not been formally evaluated. In an attempt to do this, data on HIV progression for 50,000 notional patients who became infected in the years between 1976 (assumed to be the start of the epidemic) and 2010 were simulated under various scenarios. In Scenario 1, we considered a variable called X, which was specified to be associated with more rapid progression of HIV infection. In Scenario 2, we considered a variable Y, which was specified not to be associated with more rapid progression but which tended to change in value as a result of HIV-induced immunosuppression. Variable Z, in Scenario 3, was specified to be associated with more rapid progression and to change in value when severe immunosuppression developed. Cross-sectional analyses evaluating the association between variables X, Y, and Z and the CD4 count/presence of AIDS were performed for data as of 1980, 1985, 1995, 2000, 2005, and 2010 to assess the extent to which the true role of the three variables could be ascertained. For Scenario 1, cross-sectional analyses performed on these data later in the epidemic falsely suggested that variable X was not related to HIV progression. Variable Y in Scenario 2 falsely appeared to be related to HIV progression, due to the inability of the cross-sectional design to distinguish the fact that changes in variable Y were as a result of immunosuppression and not a possible cause of it. In Scenario 3, variable Z showed a relationship with the presence of AIDS for which the typical interpretation would lead to the suggestion that its effect is in the reverse direction to that which was, in fact, the case. In conclusion, as the HIV epidemic progresses, cross-sectional studies will increasingly tend to give misleading results. Most importantly, it is incorrect to conclude that variables found to have no association with HIV disease stage in such studies are not of potential importance to pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Use of AIDS surveillance data to describe subepidemic dynamics.

BACKGROUND: Official reports on AIDS surveillance mainly consist of absolute numbers of AIDS cases or cumulative incidence rates. More detailed analyses focusing on the clusters of subepidemics within Italy seemed necessary for a better understanding and more accurate description of the epidemic. METHODS: Age-specific AIDS incidence rates were calculated with reference to resident population by sex, calendar time and geographical area. Age-standardized incidence rates, with the Italian resident population in 1990 as standard, were used to present time trends and geographical distributions. All analyses were repeated for injecting drug users, homosexual/bisexual men, heterosexual contacts and individuals with other or undetermined risk factors. RESULTS: Annual incidence rates for AIDS in Italy increased over the study period. The highest rates were observed in the North and in Sardinia, while Southern regions showed generally lower rates. This heterogeneity was more evident when examining small geographical areas (i.e. provinces). Epidemics in some of the smaller provinces, such as Imperia and Livorno (Northwestern port towns), were shown to be important in that they greatly affect AIDS incidence rates in the regions in which they are located. CONCLUSIONS: According to our analysis, the crude presentation of data from the Italian AIDS Registry is not adequate for understanding the national spread of the AIDS epidemic in terms of several local subepidemics, which may differ by size, temporal trend, and risk group composition. Classifying cases according to their place of residence, which we considered as a good proxy of the place of life, was fundamental for correctly locating these subepidemics. Furthermore, the use of age-standardized rates allowed for unbiased comparisons between regions whose population may have a different age structure and dynamics.

Acquired Immunodeficiency Syndrome↗