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Biomedical subjects

M Leal

Publications and source records attributed to M Leal.

At least 73 records · Page 4Linked to original sources
PubMed1997

Viraemia and p24 antigenaemia are independent risk factors for the emergency of a zidovudine-resistant genotype in nucleoside analogue-treated HIV-1 infection.

We aimed to determine, in an observational retrospective study, whether baseline HTV-1 RNA is an independent predictive factor for the emergence of a genotype associated with zidovudine resistance and whether previously identified predictive factors remain independent when viraemia is taken into account. Fifty nucleoside-naive HIV-1-infected individuals initiating zidovudine therapy (in 11 cases associated with didanosine) were submitted to clinical, immunological and virological monitoring at entry and every 12 weeks thereafter. The critical endpoint of the study was the influence of key baseline characteristics (CD4 cell counts, clinical stage, HIV-1 p24 antigen, virus phenotype and viraemia) upon the time to development of mutation at codon 215. The presence of serum p24 antigen, syncytium-inducing (S1) phenotype, a HIV-1 RNA load greater than the median (32495 RNA copies/ml), CD4 cell counts lower than 200/mm3 and clinical CDC category C were all baseline features associated with more rapid development of the mutant RT215 genotype in the univariate analysis. However, a multivariate Cox proportional hazard stepwise regression analysis showed that only baseline p24 antigenaemia, SI phenotype and a HIV-1 RNA load greater than 32495 RNA copies/ml were sequentially selected as independent predictive factors for the development of the mutant genotype. The present study suggests that baseline HIV-1 RNA load is an independent predictive factor for the development of a zidovudine resistance genotype. Likewise, it reinforces the independent predictive value of serum p24 antigenaemia and SI phenotype, even when viraemia is taken into account.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Acquisition of syncytium-inducing HIV-1 strains during therapy with zidovudine alone or combined with alpha interferon or didanosine.

The effect of antiretroviral treatment on HIV-1 phenotype was studied in a group of 83 nucleoside-naive patients. These initially nonsyncytium-inducing HIV-1 positive patients were followed prospectively for their HIV-1 phenotype. Syncytium-inducing variants were detected by cocultivation of peripheral blood mononuclear cells with the MT-2 T-cell line. Overall, 16 of 83 (19%) patients underwent a shift to syncytium-inducing phenotype: 11 of 67 during zidovudine treatment, 3 of 10 during zidovudine plus alpha interferon treatment, and 2 of 6 under initial zidovudine plus didanosine therapy. The results of this study demonstrate that neither zidovudine therapy alone nor combined with interferon or didanosine prevents the acquisition of syncytium-inducing strains.

Adult↗
PubMed1996

Rate of development of mutation at codon 215 of HIV-1 reverse transcriptase and its predictive factors at the time of initiation of zidovudine therapy.

The objective of the present study was to determine the rate of development of mutation at codon 215 of HIV-1 reverse transcriptase and to identify baseline characteristics associated with this mutation following initiation of zidovudine therapy. To achieve such a purpose, 80 HIV-1-infected patients starting zidovudine therapy have been submitted to clinical, immunological and virological monitoring at entry and every 12 weeks. The critical end point of the study was time to development of mutation at codon 215. The association of key baseline characteristics (CD4+ counts, clinical stage, HIV-1 p24 antigen, CD8+ counts, serum beta 2-microglobulin and virus phenotype) with the mutation at codon 215 was also investigated. A total of 38 subjects (48%) developed mutation at codon 215 during follow-up. The estimated Kaplan-Meier probability of remaining with wild genotype at 24, 48 and 96 weeks (96% CI) was 0.82 (0.73-0.90), 0.70 (0.60-0.80) and 0.53 (0.41-0.66) respectively. Univariate analysis showed that time to the development of mutation at codon 215 was positively associated with baseline p24 positivity, C clinical stage, low CD4+ count and high beta 2-microglobulin level. Only p24 antigenaemia and CD4+ count remained significantly independent predictive factors for the development of mutation at codon 215 in the Cox proportional hazard stepwise regression analysis [risk ratio (95% CI): 3.67 (1.75-7.70), P = 0.0007; 2.89 (1.17-6.72), P = 0.0073 respectively]. Thus, a continuous emergence of mutation at codon 215 was observed and HIV-1 p24 antigenaemia should be considered an independent predictor for faster development of zidovudine resistance.

Adolescent↗
PubMed1996

HIV-1 viraemia changes in patients with and without syncytium-inducing phenotype treated with nucleoside analogues: a case-control study.

The objective of the present study was to investigate the effect of the nucleoside analogue treatment on serum viraemia, CD4+ cell count and disease progression in patients with and without syncytium-inducing (SI) HIV-1 variants. To achieve this in a case-control study, 11 nucleoside-naive patients harbouring SI variants who started treatment with zidovudine or zidovudine plus didanosine were matched with 11 control patients who never formed SI variants during a follow-up of 48 weeks. The matching criteria were age, CD4+ cell count and CDC clinical category at the start of the study and exposure to the same antiretroviral treatment. During the follow-up there were no significant differences in the changes of serum HIV-1 RNA viral load and CD4+ cell counts between the two groups. In contrast, AIDS or new AIDS-defining events were observed in five SI cases but in none of the non-SI controls (P = 0.002). The emergence of a zidovudine-resistant mutation at codon 215 was observed in all the patients harbouring SI strains and in six of the subjects with non-SI variants (P = 0.03). The results of the present study show that in patients carrying SI virus, measurements of CD4+ count or RNA viral burden are neither related to the virulence of the virus strains nor able to predict the clinical course of the disease, at least under anti-retroviral drug conditions. Thus, determination of SI phenotype should be considered in the evaluation and monitoring of HIV-1 therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1996

A pilot case-control study of zidovudine compared with zidovudine plus didanosine in patients with advanced HIV-1 disease and no previous experience with antiretrovirals.

Although zidovudine (ZDV) is effective in HIV-1-infected patients, the duration of its efficacy may be short when treatment is started in advanced HIV disease. This pilot prospective case-control study was designed to evaluate the combination of ZDV plus didanosine [ddI] compared with ZDV monotherapy as an initial therapeutic strategy. 'Control' patients (ZDV monotherapy) were matched with 'case' patients (ZDV plus ddI combination therapy) according to the presence or absence of AIDS-defining criteria at entry and CD4 cell count. The case patient group consisted of 35 consecutive HIV-1-infected individuals with < or = 300 CD4 cells/mm3, no previous experience of antiretroviral therapy and who accepted treatment with a combination of ZDV plus ddI. The control patient group consisted of 35 consecutive patients with similar characteristics, but who preferred to start treatment with ZDV alone. Control patients received 250 mg ZDV bid and case patients received ZDV at the same dose plus ddI (200 mg bid). Primary study endpoints were virological (serum HIV-1 RNA) and immunological (CD4 cell count) responses. Viral phenotype (syncytium-inducing (SI) or non-syncytium-inducing (NSI)), development of mutations at codons 215, 41 and 74 and clinical progression (new AIDS-defining event or death) were also assessed. Virological and CD4 cell count responses were significantly greater and more sustained in the group treated with ZDV plus ddI than in the control group, with peak responses of -1.2 +/- 0.7 log10 versus -0.3 +/- 0.4 log10 at 1 month (P = 0.0003) and 61 +/- 52 cells/mm3 versus 19 +/- 25 cells/mm3 at 2 months (P = 0.001), respectively. In both groups the percentage of patients developing a mutation at codon 215 was around 80 per cent at 12 months. A mutation at codon 74 was detected in 30 per cent of case patients at 12 months. Five case patients (14 per cent) versus 12 control patients (34 per cent) showed signs of clinical progression (P = 0.09). In a multivariate model, clinical progression was significantly associated with a baseline

Adult↗
PubMed1996

Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data.

BACKGROUND: Combination treatment with tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed strategy especially in depressed patients unresponsive to monotherapy. Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic interactions that can result in elevated serum TCA levels. For the combinations, safety and tolerability data are lacking. METHOD: We report tolerability and safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22 patients. Most patients suffered from depression and obsessive-compulsive symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were determined. EEG, ECG, and laboratory parameters and adverse effects reported by the patients, as well as global clinical improvement, were assessed. RESULTS: Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI levels reached 500 to 1200 ng/mL in half of the patients, while corresponding levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in serum were markedly lower under comedication than under CMI monotherapy. Alterations in EEG, ECG, and laboratory parameters that had clinical relevance were rarely observed and were reversible after dose reduction of CMI. However, 2 patients developed myoclonic jerks. A majority of patients improved clinically during combination treatment. Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3. CONCLUSION: Our results suggest that comedication of fluvoxamine and clomipramine will result in markedly elevated serum clomipramine levels. Therefore, combination treatment with fluvoxamine and clomipramine should be carefully monitored by determination of serum levels of the TCA. Clinically, the pharmacokinetic interactions between fluvoxamine and clomipramine may be well tolerated in a majority of patients. However, in a few patients, higher serum levels may be associated with an increased risk of EEG changes and changes of intracardiac conductance. EEG and ECG should be used regularly to monitor comedicated patients.

Adult↗
PubMed1995

Prevalence of infection by human T-cell leukemia virus types I and II in southern Spain.

To assess the spread of human T-cell leukemia virus (HTLV) type I and II in different population groups at potential risk of infection in Spain, a total of 756 subjects were studied: 453 belonging to groups at risk for retrovirus infection, 255 with diseases potentially linked to HTLV-I/II infection and 48 immigrants from endemic areas. An HTLV-I viral-lysate enzyme immunoassay (EIA) with a recombinant transmembrane envelope protein incorporated was used to screen serum samples. Reactive specimens were confirmed by Western blot strips spiked with recombinant proteins that differentiated HTLV-I from HTLV-II. Infection was then verified by the polymerase chain reaction (PCR). Serum samples from 19 of the 756 subjects analyzed (2.5%) were reactive for HTLV by EIA. One of these was from an intravenous drug user (IVDU) in whom HTLV-II infection was confirmed by Western blot and PCR; a specimen from another IVDU showed Western blot reactivity for both retroviruses, but PCR results were negative. Lastly, Western blot confirmed the presence of HTLV in one of the immigrant subjects. Western blot did not verify HTLV infection in the remaining 16 cases, indicating a high rate of nonspecific anti-HTLV reactivity when a second-generation EIA screening test was applied. These results suggest that HTLV is present in Spain among populations at high risk for HTLV, although at a very low rate and restricted to intravenous drug users and individuals immigrating from endemic areas.

Blotting, Western↗
PubMed1995

Influence of human immunodeficiency virus type 1 infection on the natural course of chronic parenterally acquired hepatitis C.

The aim of the present study was to investigate the possible role of human immunodeficiency virus (HIV) infection in the natural course of chronic hepatitis C. Seventy-six adult patients with chronic parenterally acquired hepatitis C virus (HCV) infection examined from 1989 to 1993 were enrolled; of these 32 (42.1%) were HIV positive and 44 (57.9%) were HIV negative. Serum HCV RNA quantitation was carried out by polymerase chain reaction in a well-characterized group (n = 20; 11 HIV positive and 9 HIV negative). Distribution of histological findings in liver biopsies from both HIV-infected and noninfected patients was similar. However, within 15 years after initial HCV infection, 8 of 32 (25%) HIV-positive patients developed cirrhosis, in comparison with only 2 of 31 (6.5%) patients in the HIV-negative group (p < 0.05); similar incidences of cirrhosis were found in both patient groups within 5 and 10 years after HCV infection. Most of the HIV-negative cirrhotic patients (9 of 11) developed cirrhosis in a time interval longer than 15 years. Finally, HCV load was almost ten times higher (1 10-fold dilution) in the HIV-positive group, but this difference did not reach statistical significance in this small study population. These results suggest that HIV infection can alter the natural course of chronic parenterally acquired hepatitis C, causing an unusually rapid progression to cirrhosis.

Adult↗
PubMed1995

Emergence and clinical relevance of mutations associated with zidovudine resistance in asymptomatic HIV-1 infected patients.

The dynamics leading to the emergence of a zidovudine-resistant mutation at codon 215 of the reverse transcriptase coding region was investigated in a cohort of HIV-infected individuals who received early zidovudine therapy. Clinical implications and the role of the resistance mutation at codon 41 were also assessed. Thirty-eight initially asymptomatic HIV-infected patients with a CD4+ cell count above 400 cells/mm3 were followed for a mean period of 121 weeks (20 received zidovudine and 18 matching placebo). Specific mutations in the HIV-1 reverse transcriptase coding region conferring resistance to zidovudine were detected using a selective polymerase chain reaction. During the follow-up period a mutation at codon 215 was detected in eight (40%) of the individuals in the zidovudine group, and in two of these eight subjects, a mutation at codon 41 was found. During the study, disease progression occurred in seven of the eight (88%) patients with a mutation at codon 215, compared with 7 of 18 (39%) patients assigned to the placebo group and 3 of the 12 (25%) patients receiving zidovudine treatment who did not develop a 215-mutant strain (p < 0.05). At entry, none of the patients harbored MT-2 tropic virus. Therefore, the emergence of a zidovudine-resistant mutation at codon 215 is associated with subsequent disease progression in asymptomatic HIV-infected patients who receive zidovudine monotherapy. This association suggests that the mutation at codon 215 is involved in a loss of therapeutic efficacy and, therefore, patients should be monitored during treatment with zidovudine.

Adult↗
PubMed1994

Provirus load changes in untreated and zidovudine-treated human immunodeficiency virus type 1-infected patients.

Human immunodeficiency virus type 1 (HIV-1) provirus burden was quantified during follow-up of untreated patients and mathematically analyzed by a parameter called intrinsic rate of increase (r). There was an increase in provirus burden in patients at early stages of the infection, and the increase occurred at a similar rate in later stages of the disease. Antiviral response to zidovudine was evaluated using r. Nearly 50% of patients responded with strong decreases of r, and the rest behaved as nonresponders. Parameter r is valuable in disease prognosis, as the mean r was higher in disease progressors than in nonprogressors, and this difference was significant and more pronounced in treated patients. The zidovudine resistance mutation at codon 215 of reverse transcriptase was associated with a worse response to therapy. Absence of antiviral response and resistance mutations were more frequent in patients with lower CD4+ cell counts and higher provirus loads. These findings support a more beneficial effect of early than late therapy.

CD4-Positive T-Lymphocytes↗