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Biomedical subjects

Stefano Vella

Publications and source records attributed to Stefano Vella.

At least 37 records · Page 2Linked to original sources
PubMed2004

Changing incidence of central nervous system diseases in the EuroSIDA cohort.

A drastic decrease in incidence has been observed for most human immunodeficiency virus (HIV)-related opportunistic manifestations after use of highly active antiretroviral therapy (HAART). We assessed the trend of incidence of central nervous system (CNS) diseases in a prospective multicenter observational study involving 9,803 patients across Europe in the period 1994 to 2002 and analyzed patient and treatment variables associated with these conditions. Overall, 568 patients (5.8%) received a diagnosis of a new CNS disease. Incidence decreased significantly from 5.9 per 100 person-year in 1994 to 0.5 in 2002. Overall, the decrease was 40% per calendar year, and it was similar to that of non-CNS diseases and less evident after year 1998. In multivariable models, low CD4 cell count and high plasma viral load, but not HAART or calendar year, were significantly associated with risk to develop CNS disease, indicating that the effect of HAART was likely mediated by both improved immunological conditions and inhibition of viral replication. In contrast, use of nucleoside reverse transcriptase inhibitors, irrespective of use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors, appeared to protect specifically against acquired immunodeficiency disease syndrome dementia complex, suggesting that, in this condition, therapy might have a direct, additive effect in the CNS.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Factors influencing medication adherence beliefs and self-efficacy in persons naive to antiretroviral therapy: a multicenter, cross-sectional study.

It is widely recognized that adherence to antiretroviral therapy is critical to long-term treatment success, yet rates of adherence to antiretroviral medications are frequently subtherapeutic. Beliefs about antiretroviral therapy and psychosocial characteristics of HIV-positive persons naive to therapy may influence early experience with antiretroviral medication adherence and therefore could be important when designing programs to improve adherence to antiretroviral therapy. As part of a multicenter AIDS Clinical Trial Group (ACTG 384) study, 980 antiretroviral-naive subjects (82% male, 47% White, median age 36 years, and median CD4 cell count 278 cells/mm3) completed a self-administered questionnaire prior to random treatment assignment of initial antiretroviral medications. Measures of symptom distress, general health and well-being, and personal and situational factors including demographic characteristics, social support, self-efficacy, depression, stress, and current adherence to (nonantiretroviral) medications were recorded. Associations among variables were explored using correlation and regression analyses. Beliefs about the importance of antiretroviral adherence and ability to take antiretroviral medications as directed (adherence self-efficacy) were generally positive. Fifty-six percent of the participants were "extremely sure" of their ability to take all medications as directed and 48% were "extremely sure" that antiretroviral nonadherence would cause resistance, but only 37% were as sure that antiretroviral therapy would benefit their health. Less-positive beliefs about antiretroviral therapy adherence were associated with greater stress, depression, and symptom distress. More-positive beliefs about antiretroviral therapy adherence were associated with better scores on health perception, functional health, social-emotional-cognitive function, social support, role function, younger age, and higher education (r values = 0.09-0.24, all p < .001). Among the subset of 325 participants reporting current use of medications (nonantiretrovirals) during the prior month, depression was the strongest correlate of nonadherence ( r = 0.33, p < .001). The most common reasons for nonadherence to the medications were "simply forgot" (33%), "away from home" (27%), and "busy" (26%). In conclusion, in a large, multicenter survey, personal and situational factors, such as depression, stress, and lower education, were associated with less certainty about the potential for antiretroviral therapy effectiveness and one's perceived ability to adhere to therapy. Findings from these analyses suggest a role for baseline screening for adherence predictors and focused interventions to address modifiable factors placing persons at high risk for poor adherence prior to antiretroviral treatment initiation.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection.

BACKGROUND: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies. METHODS: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen. RESULTS: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression. CONCLUSIONS: The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.

Adult↗
PubMed2003

Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection.

BACKGROUND: It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens. METHODS: In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir. RESULTS: A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21). CONCLUSIONS: There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.

Adult↗
PubMed2003

A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease.

To compare long-term virologic benefits of antiretroviral regimens in persons with advanced human immunodeficiency virus (HIV) disease, a randomized, open-label study was conducted of 517 subjects with no or limited previous experience with antiretroviral therapy. Subjects received lamivudine plus zidovudine and indinavir (indinavir group), efavirenz plus indinavir (efavirenz + indinavir group), or nelfinavir plus indinavir (nelfinavir + indinavir group) and were monitored for 2.1 years. Virologic failure was lower in the efavirenz + indinavir group (P=.04) and higher in the nelfinavir + indinavir group (P=.006), compared with that in the indinavir group. No difference in grade 3 or 4 adverse event rates in the efavirenz + indinavir group (P=.97) and a trend toward an increased rate in the nelfinavir + indinavir group (P=.07), compared with the indinavir group, were noted. A 4-drug regimen containing efavirenz plus indinavir resulted in a superior virologic response, whereas one containing nelfinavir plus indinavir resulted in an inferior response and a greater likelihood of toxicity.

Adult↗
PubMed2003

Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation.

OBJECTIVE: The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research. DESIGN: A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model. METHODS: Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes. RESULTS: In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity. CONCLUSIONS: Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

Acrylic Resins↗
PubMed2003

Selection of resistance mutations in pregnant women receiving zidovudine and lamivudine to prevent HIV perinatal transmission.

Two zidovudine/lamivudine regimens for the prevention of HIV perinatal transmission were studied for the selection of resistance mutations. The M184V mutation was detected one week after delivery in six out of fifty women (12%) who received the regimen prepartum, intrapartum and postpartum, and was no longer present 3 months later. No nucleoside reverse transcriptase inhibitor resistance-associated mutations were detected in 50 women who received zidovudine/lamivudine intrapartum and postpartum only. No association with the risk of perinatal transmission was found.

Anti-HIV Agents↗
PubMed2003

Mitochondrial membrane hyperpolarization hijacks activated T lymphocytes toward the apoptotic-prone phenotype: homeostatic mechanisms of HIV protease inhibitors.

A decrease of mitochondrial membrane potential has been hypothesized to be a marker of apoptotic cells, including activated T lymphocytes. It was recently demonstrated that HIV protease inhibitors, independently from any viral infection, can hinder lymphocyte apoptosis by influencing mitochondrial homeostasis. To analyze the mechanisms underlying these effects, a specific study was undertaken in both resting and activated human PBL exposed to either receptor (e.g., anti-Fas)- or nonreceptor (e.g., radiation)-mediated apoptotic stimuli. T cell activation was found to be accompanied by a significant increase in mitochondrial membrane potential, or hyperpolarization, which was undetectable in resting cells. We also detected apoptotic hindering by HIV protease inhibitors only in activated T lymphocytes. This was apparently due to the ability of these drugs to block activation-associated mitochondria hyperpolarization, which, in turn, was paralleled by an impairment of cell cycle progression. Remarkably, protease inhibitors also prevented zidovudine-mediated mitochondrial toxicity. Finally, HIV-infected cells from naive patients behaved identically to activated T cells, displaying hyperpolarized mitochondria, while lymphocytes from patients under highly active antiretroviral therapy (which included HIV protease inhibitors) seemed to react as resting cells. Altogether these results clearly indicate that the hyperpolarization state of mitochondria may represent a prerequisite for the sensitization of lymphocytes to the so-called activation-induced cell death. They also suggest that HIV protease inhibitors, by interfering with induction of the mitochondrial hyperpolarization state, can result in cell survival even independent of any viral infection.

Adult↗
PubMed2003

Replication capacity, biological phenotype, and drug resistance of HIV strains isolated from patients failing antiretroviral therapy.

The fitness of human immunodeficiency virus (HIV) in vivo depends on the interaction of a multitude of viral and host factors. The aim of this study was to analyze the biological phenotype and the intrinsic capacity of the HIV isolates with drug-resistance mutations to replicate efficiently in the absence of drugs. An open label multicenter cross-sectional study was undertaken on 28 HIV-infected patients failing antiretroviral treatment. The subjects were studied for CD4+ cell count, HIV viral load, syncytium-inducing phenotype, genotypic drug-resistance assay, and replication capacity of HIV isolates assessed by co-culture assay. All HIV isolates showed a decreased replication capacity compared with wild-type strains. The lowest replication capacity was detected in HIV strains with more than five drug-resistance mutations. The highest replication capacity was observed in strains carrying the K103N and Y181C primary mutations that emerged after treatment with non-nucleoside analogue inhibitors. Isolates with R5 biological phenotype had a higher number of resistant mutations than X4 isolates (P = 0.004). Particularly, the R5 phenotype was detected in all 6 isolates with more than 14 drug-resistance mutations. Patients with R5 strains had plasma viral load similar to patients with X4 strains, but marginally higher CD4+ cell counts, and their HIV isolates had significantly lower replication capacity of HIV isolates (P = 0.008). No patient carrying HIV with a maintained replication capacity had a viral load less than 30,000 copies/ml. In patients failing HAART, the detection of HIV isolates with the R5 biological phenotype correlates with CD4+ cell count, an impaired replication capacity, and a high number of drug-resistance mutations.

Anti-HIV Agents↗
PubMed2003

Future treatment perspectives.

Progress in antiretroviral therapy has resulted in dramatic achievements, such as the considerable reductions in morbidity and mortality observed in HIV-infected patients living in western countries, and new challenges, including the awareness of the long-term toxicities of antiretroviral (ARV) drugs and of viral cross-resistance. Changes in treatment guidelines have occurred as a result of data obtained from clinical trials but also of a better knowledge of the pathophysiology of the disease. Recommendations on when to start therapy in asymptomatic, chronically infected individuals have shifted to a more conservative approach. The availability of new assays, particularly resistance testing, is improving the ability of physicians to select individualized treatment regimens for patients with virological failure. The availability of new ARV drugs and the evaluation of new therapeutic concepts (including treatment simplification and treatment interruptions) may impact future directions of anti-HIV therapy. New drugs in development show promising antiviral activity, including activity against strains that are resistant to available agents, and this may help to circumvent cross-resistance.

Anti-HIV Agents↗
PubMed2003

Drug-associated resistance mutations in plasma and peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected patients for whom highly active antiretroviral therapy is failing.

In 32 patients for whom highly active antiretroviral therapy was failing, a good agreement between drug resistance-associated mutations in plasma and peripheral blood mononuclear cells (PBMCs) was found (k = 0.85). The mutations with the lowest agreement were 20R, 63P, and 84V in the protease gene and 184V in the reverse transcriptase gene. In eight patients, primary drug resistance mutations were detected only in PBMCs.

Adult↗
PubMed2003

High prevalence of M184 mutation among patients with viroimmunologic discordant responses to highly active antiretroviral therapy and outcomes after change of therapy guided by genotypic analysis.

Whether highly active antiretroviral therapy (HAART) should be modified in patients with persistent increases in CD4(+) T cells despite detectable viral loads is an unresolved question. Forty-three heavily pretreated human immunodeficiency virus (HIV)-infected patients with virologic failure during HAART were studied before a change of therapy guided by genotypic analysis and during follow-up. Patients with an increase in CD4(+) cell count (>100 cells/ml) over pre-HAART values were considered to be discordant patients (20 individuals), whereas patients with a lower increase or no increase in CD4(+) cell count were considered failing patients (23 individuals). Based on univariate analysis, a high CD4(+) cell count before antiretroviral treatment, homosexual behavior as a risk factor for HIV infection, reduced drug exposure to nonnucleoside reverse transcriptase inhibitors, low replicative capacity of HIV isolates, and more frequent detection of HIV isolates with a non-B subtype, an R5 biological phenotype, and M184V and T215Y/F mutations were factors associated with a discordant response to HAART. Based on multivariate analysis, only the M184V mutation remained significantly associated with a viroimmunologic discordant response (odds ratio, 25.48; 95% confidence interval, 1.43 to 453.93). No difference in lamivudine exposure was found between discordant (95%) and failing (91%) patients. Twelve months after the genotypic analysis-guided change of therapy, 3 discordant (15%) and 6 failing patients (26%) achieved undetectable viral loads (<50 copies/ml), whereas in patients with HIV RNA loads of >500 copies/ml, discordant responses were observed in 5 out of 15 discordant patients and in 4 out of 16 failing patients. A relationship between the M184V mutation and a viroimmunologic discordant response to HAART was found. After the genotypic analysis-driven change of therapy, similar rates of virologic suppression were detected in the two groups.

Antiretroviral Therapy, Highly Active↗
PubMed2003

CD4+ lymphocyte increases in HIV patients during potent antiretroviral therapy are dependent on inhibition of CD8+ cell apoptosis.

Although suppression of apoptosis contributes to immune-reconstitution during potent antiretroviral therapy, its relationship with the majors indicators of response to therapy, that is, changes in CD4(+) cell counts and in viral loads (VL), is still debated. We extended our previous study by collecting data on the relationships among apoptosis and immunological and virological parameters during a long-term follow-up of HIV patients with an overall positive response to potent antiretroviral therapy. We report results from 15 patients who completed two years of therapy. In a smaller group of patients, we focused our attention on investigating the specific contribution of the CD8(+) subset in the overall changes in lymphocyte apoptosis, which occur concomitantly with the response to the therapy. Our data, while again confirming that inhibition of PBMC apoptosis is a phenomenon strictly related to a positive response to potent antiretroviral therapy, suggest that CD4(+) cell rescue is not directly dependent on inhibition of CD4(+) cell apoptosis but rather on that of the CD8(+) subset.

Anti-HIV Agents↗
PubMed2003

Changes in viral load in people with virological failure who remain on the same HAART regimen.

OBJECTIVES: To assess the rate of change in viral load and CD4 count over time in HIV-infected patients experiencing virological failure on a HAART regimen. DESIGN: Study population included patients from EuroSIDA, a large, multicentre, observational study enrolling HIV-infected patients across Europe. METHODS: Median change in viral load and CD4 count per month were estimated using the viral load and CD4 measurements obtained over a 12-month period after confirmed virological failure between 3 and 4 log10 copies/ml in a population of 488 HIV-infected patients who were left on a failing HAART regimen. RESULTS: The estimated median viral load change in our study population was 0.024 log10 copies/ml per month, statistically different from 0 (P=0.0001). In 20.9% of the patients studied viral load showed a tendency to decrease, in 47.8% showed a tendency to increase by a positive rate no higher than 0.04 log10 copies/ml per month and in the remaining 31.3% showed a tendency to increase by a rate greater than 0.04 log10 copies/ml per month. On average, CD4 counts were estimated to remain stable (decrease at a slow rate of about -0.53 cells/microl per month). CONCLUSIONS: In patients that remained on a stable, but virologically failing HAART regimen (with viral load ranging 1000-10000 copies/ml), the viral load over the ensuing 12-month period increased at a relatively slow rate. In contrast, the CD4 count remained stable, possibly because of partial but sustained viral suppression below the viral load natural set-point. The time-course of selecting more replication-competent virus in patients with virological failure remains to be fully clarified.

Adult↗