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Biomedical subjects

S Vella

Publications and source records attributed to S Vella.

At least 73 records · Page 4Linked to original sources
PubMed1998

Phase II controlled trial of post-exposure immunization with recombinant gp160 versus antiretroviral therapy in asymptomatic HIV-1-infected adults. VaxSyn Protocol Team.

OBJECTIVE: To alter the natural course of HIV-1 infection by inducing or potentiating immune responses to HIV-1 envelope glycoprotein. DESIGN: Multicentre, double-blind, three-arm, placebo-controlled study. SETTING: Outpatients attending clinics in two University Hospitals. PATIENTS: Ninety-nine asymptomatic HIV-1-infected adults with CD4+ T-cell counts > 400 and < 600 x 10(6)/l and no previous antiretroviral therapy were included. INTERVENTIONS: Patients were randomly assigned to three groups treated with: (i) gp160 in alum over a 2-year period in combination with placebo for the full study duration (n = 32); (ii) gp160 in alum over a 2-year period in combination with zidovudine for the full study duration (n = 34); and (iii) alum over a 2-year period in combination with zidovudine for the full study duration (n = 33). RESULTS: Immunotherapy was well tolerated and no significant differences in disease progression were seen in the treatment groups. The majority of patients (85%) receiving gp160 showed persistent lymphoproliferative responses to the immunogen and to a different Env antigen preparation. CD4+ cell count changes in patients receiving zidovudine alone were significantly higher than those seen in patients receiving immunotherapy alone after 1 year of treatment. Zidovudine administration was associated with initial transient reduction of plasma viraemia. CONCLUSIONS: Prolonged immunization with a soluble HIV-1 subunit provided no benefit to asymptomatic HIV-1-infected patients and was inferior to zidovudine monotherapy. Furthermore, immunization with gp160 shortened the duration of the transient viral load reduction induced by zidovudine.

AIDS Vaccines↗
PubMed1998

A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.

CONTEXT: Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA. OBJECTIVE: To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine. DESIGN: Double-blind, controlled, randomized trial. SETTING: University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS). PATIENTS: Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL). INTERVENTION: Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine. MAIN OUTCOME MEASURE: Plasma HIV-1 RNA. RESULTS: Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). CONCLUSIONS: Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.

Adult↗
PubMed1998

Survival in 2367 zidovudine-treated patients according to use of other nucleoside analogue drugs. The EuroSIDA Study Group.

To evaluate survival according to use of different nucleoside drugs in a routine clinical setting, we studied a large group of zidovudine-treated patients seen in clinics across Europe. A total of 3128 subjects was recruited to the observational, prospective EuroSIDA study in May 1994. These were consecutive patients (up to a predefined limit) seen at outpatient clinics in 37 centers from 16 European countries and followed at 6-month intervals by use of standardized forms completed by clinicians at the respective centers. This report concerns 2367 subjects who began antiretroviral therapy with a regime that included zidovudine either before study entry or during the course of follow-up. Cox proportional hazards models were fitted, with use of other antiretroviral drugs, CD4 count, and date of development of AIDS fitted as time-dependent covariates. Survival times from start of therapy were left truncated at study entry to avoid survival bias. In addition to zidovudine, antiretroviral drugs used included didanosine (ddI) (n = 1119; median 1.6 years after starting zidovudine), dideoxycytidine (ddC) (n = 592; median 1.9 years after starting zidovudine), stavudine (d4T) (n = 241; median 2.9 years after starting zidovudine) and lamivudine (3TC) (n = 33 ; median 2.7 years after starting zidovudine). Of the 2367 patients, 613 died during follow-up. Overall, risk of death was reduced in those zidovudine-treated patients who began at least one other nucleoside analogue drug with or after taking zidovudine (relative hazard [RH], 0.61; 95% confidence interval [CI], 0.51-0.72, adjusting for CD4 count, development of AIDS, and age). Fitting each drug separately, there was a larger association with reduced mortality for starting 3TC (RH, 0.41; 95% CI, 0.28-0.62) than for starting ddl (RH, 0.79; 95% CI, 0.67-0.93), ddC (RH, 0.74; 95% CI, 0.59-0.92) or d4T (RH, 0.67; 95% CI, 0.49-0.91). These results suggest that the beneficial effect of nucleoside combination therapy identified in controlled trials can be seen in routine clinical practice.

Adult↗
PubMed1998

Saquinavir delays the emergence of zidovudine resistance in HIV-1 seropositive patients treated with combination therapy.

During a randomized double-blind study to assess the antiviral activity of saquinavir (SQV) alone or in combination with zidovudine (ZDV), the emergence of phenotypic resistance was evaluated in 44 patients treated with SQV (13 subjects), ZDV (14 subjects), and SQV plus ZDV (17 subjects). A significant (P< 0.05) lower CD4+ cell count and higher HIV RNA copy number at entry were found in six patients who developed resistant viral strain (3 to ZDV and 3 to SQV) during the first 4 months of treatment. After 1 year, drug-resistant strains (12 to ZDV and 14 to SQV) were isolated in 26 out of 37 patients. A significant higher number of patients treated with ZDV alone (10/13) harbored ZDV-resistant strains compared to patients treated by combination therapy (2/13); whereas more than 50% of patients had SQV-resistant strains aside from treatment. Early SQV-resistant strains were isolated in a limited number of patients treated with SQV alone (3/13). The rates of emergence of resistant strains during ZDV or SQV monotherapies are comparable. Combination therapy may delay the emergence of phenotypic resistance to either drugs in the short term and to ZDV, but not to SQV, at least after 1 year.

Anti-HIV Agents↗
PubMed1998

Frequency and determinants of use of antiretroviral and prophylactic therapies against Pneumocystis carinii Pneumonia (PCP) before AIDS diagnosis in Italy.

To determine the frequency and the determinants of use of antiretroviral drugs and prophylaxis for Pneumocystis carinii Pneumonia (PCP) among HIV-infected individuals before AIDS diagnosis, a questionnaire was sent to all physicians reporting at least one AIDS case during the first six months of 1994 to the Italian National AIDS Registry. Information on cases diagnosed between 1 January and 31 March 1995 was collected. Information was obtained for 878 (66.4%) of the 1323 persons with AIDS: 447 (50.9%) had received antiretroviral drugs and 343 (39.1%) PCP prophylaxis, whereas 303 cases (34.5%) had received both. Individuals who became aware of being HIV-positive shortly before AIDS diagnosis were less likely to have started antiretroviral therapy (adjusted odds ratio (AOR): 0.05, 95% CI: 0.03-0.09). Homosexual men and heterosexuals were more likely to begin therapy (AOR: 1.40, 95% CI: 0.83-2.37 and AOR: 1.79, 95% CI: 1.05-3.05, respectively) compared to injecting drug users. Individuals living in Southern Italy and foreigners were less likely to start therapy (AOR: 0.75, 95% CI: 0.49-1.16 and AOR: 0.40, 95% CI: 0.15-1.09, respectively) compared to those living in Northern Italy. Results were similar for PCP prophylaxis. Lack of awareness of HIV infection, HIV exposure category, and geographical area were the most important factors associated with treatment before AIDS diagnosis.

Adolescent↗
PubMed1998

HIV treatment--a rational approach to the use of antiretroviral agents.

Over the last 2 years, advances in many areas of HIV clinical research and data on the effectiveness of potent combination therapy have substantially influenced the overall perspective of long-term management of HIV disease. However, the progress against HIV also came as a result of the better understanding of HIV pathogenesis. Research work in basic science has contributed considerably to obtain a clearer picture of the mechanisms of HIV infection, mainly through the understanding of key steps in the dynamics and kinetics of viral replication in vivo. Molecular biology also revealed much about the mechanisms of HIV virulence and the emergence of drug resistance. This article will give a short overview of the most recent advances in the field.

Anti-HIV Agents↗
PubMed1998

Saquinavir. Clinical pharmacology and efficacy.

Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.

Anti-HIV Agents↗
PubMed1997

Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. EuroSIDA Study Group.

Little is known about how widely HIV-related drugs are used outside controlled clinical trials. We therefore assessed factors associated with use of antiretroviral (ARV) therapy and primary prophylactic regimens to prevent HIV-associated opportunistic infections. Baseline data from a prospective study from May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count <500 cells/microl, followed in 37 centers from 16 European countries, were analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV drug at the time of the study. ARV therapy was more frequently used among patients from southern and central Europe as compared with patients from northern Europe, especially among patients with CD4 counts >200 cells/microl (73%, 57%, and 42%, respectively, p < 0.0001). Of patients on ARV therapy, 34% received open-label combination therapy. This proportion was higher in central Europe compared with other regions (27%, 50%, and 31% for southern, central, and northern Europe, respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/microl, without marked regional differences. In patients without esophageal candidiasis or other invasive fungal infections, antifungal drugs were far less frequently used in patients from southern and central Europe compared with patients from northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of patients with a CD4 count <100 cells/microl received rifabutine as primary prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies are used differently in different parts of Europe, whereas primary PCP prophylaxis is uniformly administered to most at-risk patients. U.S. recommendations on the use of antimycobacterial prophylaxis have not been implemented in Europe.

AIDS-Related Opportunistic Infections↗
PubMed1997

[PFAPA syndrome: periodic fever, adenitis, pharyngitis and aphthous stomatitis].

A syndrome involving periodic fever, pharyngitis, adenitis and aphthous stomatitis is described in 8 children. Attacks are characterized by abrupt onset of fever and, in addition to the above symptoms, by malaise, headache and abdominal pain. Mild leukocytosis and elevation of the erythrocyte sedimentation rate are found in the laboratory. Patients exhibit normal growth and development and are otherwise healthy. PFAPA is clinically benign, with no long-term sequelae. Recognition and diagnosis of the syndrome eliminate the need for intensive work-up. The cause remains unknown. No evidence linking bacterial, viral, or fungal pathogens to this syndrome has been found. No patient has exhibited atypical lymphocytosis or neutropenia, and all patients had normal levels of immunoglobulin. All had received antibiotics early in the course of their illness but without effect. Cimetidine has been discussed in the literature as a possible treatment, but the results are controversial.

Child, Preschool↗
PubMed1997

Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel.

OBJECTIVE: To provide current recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease. PARTICIPANTS: The original International AIDS Society-USA 13-member panel representing international expertise in antiretroviral research and care of patients with HIV infection. EVIDENCE: The following were considered: Newly available clinical and basic science study results, including phase 3 controlled trials; clinical, virological, and immunologic end-point data; interim analyses of studies presented at national and international research conferences; studies of HIV pathophysiology; and expert opinions of panel members. Recommendations were limited to the drugs available in mid 1997. PROCESS: The full panel met on a regular basis (July 1996, September 1996, November 1996, January 1997, and April 1997) since the publication of its initial recommendations in mid 1996 to review new research reports and interim results. The panel discussed whether and how new information changed its initial recommendations. The recommendations contained herein were determined by group consensus. CONCLUSIONS: New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence. The plasma viral load is a crucial element of clinical management for assessing prognosis and the effectiveness of therapy, and such testing must be done properly. Treatment failure is most readily indicated by a rising plasma HIV RNA level and should be confirmed prior to a change of treatment. Therapeutic approaches must be updated as new data, particularly on the long-term clinical effect of aggressive antiretroviral treatment, continue to emerge.

Anti-HIV Agents↗
PubMed1997

Correlation between changes in plasma HIV RNA levels and in plasma infectivity in response to antiretroviral therapy.

We evaluated the degree of correlation between the variation of different HIV-1 viral load measures in response to antiretroviral therapy. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for plasma HIV-RNA, and HIV plasma infectivity titration, were performed on prospective samples obtained from 86 antiretroviral-naive patients with symptomatic infection and CD4+ < 300/mm3, enrolled in a randomized double-blind trial of the HIV protease inhibitor saquinavir (SQV) in combination with zidovudine (ZDV). Subjects were stratified according to plasma virus infectivity and examined for correlations between distinct response categories with respect to CD4 count and HIV RNA copy number changes. Infectious virus could be titrated in 72% of patients at baseline. A significant reduction (< 1 log10) in HIV plasma infectivity titer was observed during the study in 69% of these patients. The reduction in plasma infectivity was a good predictor of sustained CD4+ cell increases and of sustained decrease in HIV RNA plasma copies. A decrease of at least 0.5 log10 in HIV RNA copy number was observed in 82% of the treated patients. A good correlation was found between HIV plasma infectivity titer and plasma HIV RNA copy number variations (p < 0.001). However, 10 of 17 patients with unchanged plasma infectivity titer showed a significant reduction in HIV RNA copies. While a good correlation was found between plasma infectivity and RNA plasma copies variations, only a minor correlation was found between CD4+ cell count variation and plasma infectivity titer variation. However, reduction in plasma infectivity was a very good predictor of high CD4 changes.

Anti-HIV Agents↗
PubMed1997

Mutation of ornithine transcarbamylase (H136R) in a girl with severe intermittent orotic aciduria but normal enzyme activity.

Ornithine transcarbamylase deficiency shows X-linked inheritance with partial dominant expression in carrier females. We studied a girl with intermittent severe orotic aciduria and mild hyperammonaemia despite apparently normal enzyme activity in the liver. Sequence analysis of all 10 exons of the ornithine transcarbamylase gene revealed a novel A-->G exchange (A502G) in exon 5 which changes His-136 to arginine in the ornithine transcarbamylase protein. Km values for carbamyl phosphate and ornithine determined in the patient's liver were comparable to those of wild-type enzyme but, unlike the wild-type enzyme, the mutant enzyme was unstable upon freezing and thawing. Electron microscopy revealed several giant mitochondria with paracrystalline inclusions. The results are compatible with the assumption that the mutant enzyme cannot form a functional complex with carbamyl phosphate synthetase and the ornithine carrier, resulting in decreased availability of substrates and diminished enzyme activity in vivo.

Ammonia↗
PubMed1997

High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication.

High-dose nevirapine treatment has been reported to confer sustained antiretroviral effects, despite a rapid development of resistance. The use of this strategy was evaluated in 20 previously untreated human immunodeficiency virus type 1 (HIV-1) p24 antigenemic persons with CD4 cell counts between 100 and 500/mm3. Treatment consisted of 400 mg of nevirapine, after a 2-week lead-in dose of 200 mg. Rash was the most frequently reported adverse event, occurring in 25%. While sustained declines in p24 antigen levels were observed in the majority, serum HIV-1 RNA load and CD4 cell counts returned to baseline values within 12 weeks in virtually all subjects. The resistance-conferring tyrosine-to-cysteine substitution at reverse transcriptase position 181 was detected after 4 weeks in most subjects. These observations suggest that plasma drug levels attained with high-dose nevirapine were not sufficient to inhibit nevirapine-resistant virus, although they were approximately 2-fold higher than reported IC50 values of resistant virus.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Survival of AIDS patients according to type of AIDS-defining event. The AIDS in Europe Study Group.

BACKGROUND: There are known to be wide differences in the prognosis of patients with a diagnosis of AIDS. In this study of 6578 patients with AIDS form 17 European centres, we develop a ranking of AIDS-defining illnesses, and determine how well this ranking holds after adjustment for potential confounding variables. METHODS: Survival from each AIDS-defining event was calculated and ranked using Kaplan-Meier estimation of median survival. Cox proportional hazards models with each disease modelled as a time dependant covariate were used to determine the risk of death after each diagnosis, before and after adjustment for potential confounders. RESULTS: Median survival after an initial AIDS-defining diagnosis of progressive multifocal leukoencephalopathy and malignant lymphoma was particularly poor (2 and 5 months respectively), while the longest median survival occurred after initial AIDS-defining illnesses of Kaposi's sarcoma and extrapulmonary tuberculosis (17 and 22 months respectively) Patients diagnosed with a primary brain lymphoma had shorter median survival times than patients with a peripheral lymphoma (median survival of 1 month and 4 months respectively P < 0.0001). In general, median survival in patients with cutaneous Kaposi's sarcoma (skin, oral) was between two and four times longer than patients with systemic involvement The ranking of diseases was found to be generally similar after adjustment for all potential confounders. CONCLUSIONS: AIDS-defining events can be grouped into three categories with median survival after diagnosis of < 6 months. 6-12 months and > 12 months. The assigned ranking of disease would not be altered by prognostic factors such as age or CD4 lymphocyte count. These results have important implications in the design of clinical trials and patient management.

AIDS-Related Opportunistic Infections↗
PubMed1997

A randomized trial (ISS 902) of didanosine versus zidovudine in previously untreated patients with mildly symptomatic human immunodeficiency virus infection.

In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.

Acquired Immunodeficiency Syndrome↗