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Biomedical subjects

F Clavel

Publications and source records attributed to F Clavel.

At least 19 recordsLinked to original sources
PubMed2002

Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

Adult↗
PubMed2001

Comparison of genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 isolates from patients treated with stavudine and didanosine or zidovudine and lamivudine.

Sequencing of reverse-transcriptase genes and recombinant virus assays were performed on paired isolates from antiretroviral drug-naive patients randomized to stavudine and didanosine (group 1; n = 21) or zidovudine and lamivudine (group 2; n = 21) at baseline and after > or = 12 months of follow-up. The T215Y mutation emerged in 13 (61.9%) and 2 (9.5%) isolates in groups 1 and 2, respectively (P < .0001). Furthermore, in group 1, mutations associated with multidideoxynucleoside resistance were selected in 3 isolates. In group 2, all isolates carried the M184V mutation. The median fold changes in susceptibilities to zidovudine, stavudine, and lamivudine were 16.4 and 1, 2.2 and 0.6, and 4.5 and > 38 in groups 1 and 2, respectively (P < .0001, all comparisons). These results suggest that the combination of stavudine and didanosine is associated more frequently with the emergence of zidovudine resistance and a decrease in susceptibility to stavudine than the combination of zidovudine and lamivudine.

Adult↗
PubMed2001

Primary and recombinant HIV type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues.

Preserved peripheral CD4+ T cell counts despite virologic failure in patients undergoing protease inhibitor (PI)-containing antiviral regimens are a frequent occurrence in human immunodeficiency virus (HIV) disease. One hypothesis to explain the relative sparing of CD4+ T cells is that HIV strains exhibiting PI resistance concomitantly are attenuated in terms of cytopathicity for mature T cells. To test this hypothesis, we used a three-dimensional human tonsil histoculture microenvironment to assess the pathogenic potential of a panel of primary and recombinant HIV-1 strains derived from patients experiencing PI failure. All the viruses tested replicated efficiently in these cultures and, in some cases, better than comparable wild-type viral isolates. Furthermore, the PI-resistant strains depleted CD4+ T cells potently and comparably with wild-type isolates in these ex vivo lymphoid tissues. These results demonstrate that PI-resistant viruses are not inherently less pathogenic for mature T cells. Therefore, the sustained peripheral lymphocyte counts in patients with selective virologic failure may be due to specific defects in viral replication in other cell compartments or to an undefined host adaptation to viral infection during PI therapy.

CD4-Positive T-Lymphocytes↗
PubMed2001

Discordant increases in CD4+ T cells in human immunodeficiency virus-infected patients experiencing virologic treatment failure: role of changes in thymic output and T cell death.

Some patients infected with human immunodeficiency virus (HIV) who are experiencing antiretroviral treatment failure have persistent improvement in CD4+ T cell counts despite high plasma viremia. To explore the mechanisms responsible for this phenomenon, 2 parameters influencing the dynamics of CD4+ T cells were evaluated: death of mature CD4+ T cells and replenishment of the CD4+ T cell pool by the thymus. The improvement in CD4+ T cells observed in patients with treatment failure was not correlated with spontaneous, Fas ligand-induced, or activation-induced T cell death. In contrast, a significant correlation between the improvement in CD4+ T cell counts and thymic output, as assessed by measurement of T cell receptor excision circles, was observed. These observations suggest that increased thymic output contributes to the dissociation between CD4+ T cell counts and viremia in patients failing antiretroviral therapy and support a model in which drug-resistant HIV strains may have reduced replication rates and pathogenicity in the thymus.

Adult↗
PubMed2001

Impaired replication of protease inhibitor-resistant HIV-1 in human thymus.

Many HIV-1-infected patients treated with protease inhibitors (PI) develop PI-resistant HIV-1 variants and rebounds in viremia, but their CD4+ T-cell counts often do not fall. We hypothesized that in these patients, T-cell counts remain elevated because PI-resistant virus spares intrathymic T-cell production. To test this, we studied recombinant HIV-1 clones containing wild-type or PI-resistant protease domains, as well as uncloned isolates from patients, in activated peripheral blood mononuclear cells, human thymic organ cultures and human thymus implants in SCID-hu Thy/Liv mice. In most cases, wild-type and PI-resistant HIV-1 isolates replicated to similar degrees in peripheral blood mononuclear cells. However, the replication of PI-resistant but not wild-type HIV-1 isolates was highly impaired in thymocytes. In addition, patients who had PI-resistant HIV-1 had abundant thymus tissue as assessed by computed tomography. We propose that the inability of PI-resistant HIV-1 to replicate efficiently in thymus contributes to the preservation of CD4+ T-cell counts in patients showing virologic rebound on PI therapy.

Adult↗
PubMed2001

Determination of coreceptor usage of human immunodeficiency virus type 1 from patient plasma samples by using a recombinant phenotypic assay.

We developed a recombinant virus technique to determine the coreceptor usage of human immunodeficiency virus type 1 (HIV-1) from plasma samples, the source expected to represent the most actively replicating virus population in infected subjects. This method is not subject to selective bias associated with virus isolation in culture, a step required for conventional tropism determination procedures. The addition of a simple subcloning step allowed semiquantitative evaluation of virus populations with a different coreceptor (CCR5 or CXCR4) usage specificity present in each plasma sample. This procedure detected mixtures of CCR5- and CXCR4-exclusive virus populations as well as dualtropic viral variants, in variable proportions. Sequence analysis of dualtropic clones indicated that changes in the V3 loop are necessary for the use of CXCR4 as a coreceptor, but the overall context of the V1-V3 region is important to preserve the capacity to use CCR5. This convenient technique can greatly assist the study of virus evolution and compartmentalization in infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Changes in human immunodeficiency virus type 1 populations after treatment interruption in patients failing antiretroviral therapy.

Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease that confer resistance to antiretroviral agents are usually accompanied by a reduction in the viral replicative capacity under drug-free conditions. Consequently, when antiretroviral treatment is interrupted in HIV-1-infected patients harboring drug-resistant virus, resistant quasi-species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantification of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persist in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of therapy and for whom conventional genotyping had revealed an apparent total reconversion to wild-type virus, minority populations expressing these mutations, representing 0.1 to 21% of total virus, were still detectable in 9 cases. Kinetic studies demonstrated that viruses expressing resistance mutations could be detected for >5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutations present in the resistant viruses prior to treatment interruption and appeared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance. Thus, following the interruption of treatment, viral populations containing resistance mutations can persist for several months after the time when conventional genotyping techniques detect only wild-type virus. These populations include viral strains with only some of the resistance mutations initially present, strains that presumably express better fitness under drug-free conditions.

Anti-HIV Agents↗
PubMed2000

Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug.

Human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors (PI) is a major obstacle to the full success of combined antiretroviral therapy. High-level resistance to these compounds is the consequence of stepwise accumulation of amino acid substitutions in the HIV-1 protease (PR), following pathways that usually differ from one inhibitor to another. The selective advantage conferred by resistance mutations may depend upon several parameters: the impact of the mutation on virus infectivity in the presence or absence of drug, the nature of the drug, and its local concentration. Because drug concentrations in vivo are subject to extensive variation over time and display a markedly uneven tissue distribution, the parameters of selection for HIV-1 resistance to PI in treated patients are complex and poorly understood. In this study, we have reconstructed a large series of HIV-1 mutants that carry single or combined mutations in the PR, retracing the accumulation pathways observed in ritonavir-, indinavir-, and saquinavir-treated patients. We have then measured the phenotypic resistance and the drug-free infectivity of these mutant viruses. A deeper insight into the evolutionary value of HIV-1 PR mutants came from a novel assay system designed to measure the replicative advantage of mutant viruses as a function of drug concentration. By tracing the resultant fitness profiles, we determined the range of drug concentrations for which mutant viruses displayed a replicative advantage over the wild type and the extent of this advantage. Fitness profiles were fully consistent with the order of accumulation of resistance mutations observed in treated patients and further emphasise the key importance of local drug concentration in the patterns of selection of drug-resistant HIV-1 mutants.

Amino Acid Substitution↗
PubMed1999

Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies.

OBJECTIVE: To assess the patterns of HIV phenotypic cross-resistance to protease inhibitors (PI) in patients experiencing viral load rebound on combination therapy including a PI. METHODS: Phenotypic analysis of sensitivity to indinavir, nelfinavir, saquinavir, ritonavir and amprenavir was carried out using a single-cycle recombinant virus assay. Viral protease was sequenced by automated dideoxynucleotide chain termination. RESULTS: Of the 108 patients studied, 68 had received indinavir, 50 ritonavir, 25 saquinavir and eight nelfinavir. The majority (71%) had received only one PI. The incidence of cross-resistance between indinavir, nelfinavir, ritonavir and saquinavir was high (60-90%). Cross-resistance to amprenavir was less frequent (37-40%). However there was some correlation between levels of sensitivity to amprenavir and indinavir (r2 = 0.34; P < 0.01). Conversely, the correlation between levels of sensitivity to indinavir and saquinavir was poor (r2 = 0.25), particularly for patients who had not received saquinavir. The degree of cross-resistance correlated with the level of resistance and with the total number of mutations in the protease gene (P < 0.05, chi square test) but could not be significantly correlated to any one particular mutation or combination of mutations. Mutation 184V was significantly associated with cross-resistance to amprenavir, with no mutations at codon 50 observed, while mutations associated with cross-resistance to saquinavir differed according to the treatment received. CONCLUSIONS: These results suggest that, although the total number of protease mutations correlates with the degree of cross-resistance, the specific mechanisms accounting for primary resistance and for cross-resistance may be different.

Anti-HIV Agents↗
PubMed1999

Transmission of antiretroviral-drug-resistant HIV-1 variants.

BACKGROUND: Resistance of HIV-1 to antiretroviral drugs is the main cause of antiretroviral-treatment failure. We assessed the transmission of drug-resistant variants among individuals with primary HIV-1 infection. METHODS: Population-based sequencing of the viral reverse-transcriptase and protease genes derived from plasma viral RNA was done in 82 consecutive individuals with documented primary HIV-1 infection from January, 1996, to July, 1998. Phenotypic resistance to protease inhibitors was assessed by recombinant virus assay in individuals with two or more mutations associated with resistance to protease inhibitors. FINDINGS: Zidovudine-resistance mutations were detected in seven (9%) of 82 individuals. Mutations associated with resistance to other reverse-transcriptase inhibitors (RTIs) were detected in two individuals. Primary-resistance mutations associated with protease inhibitors (V82A, L90M) were detected in three (4%) of 70 individuals; two of these had also RTI-resistance mutations. Decreased sensitivity to three or four protease inhibitors was seen in three individuals, one of whom was infected with HIV-1 variants that harboured 12 mutations associated with resistance to multiple RTI and protease inhibitors. INTERPRETATION: To introduce the best antiretroviral treatment, resistance testing should be done in recently HIV-1-infected individuals.

Adolescent↗
PubMed1999

Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy.

OBJECTIVE: to assess the safety and efficacy of a combination of ritonavir, efavirenz and two recycled nucleosides in patients who failed on a conventional triple-drug regimen including indinavir or ritonavir. METHODS: An open label study of ritonavir (100 mg twice daily), saquinavir (1000 mg twice daily), efavirenz (600 mg per day) and nucleoside analogues in 32 saquinavir- and efavirenz-naive protease inhibitor-experienced patients. Patients were included on the basis of plasma levels of HIV RNA above 5000 copies/ml while on conventional antiretroviral therapy. Phenotypic resistance and genotypic resistance mutations to saquinavir were assessed at baseline. Peak and trough plasma levels of saquinavir were monitored throughout the study. RESULTS: Median CD4 cell counts and median plasma HIV RNA at baseline were 258 x 10(6)/l and 4.31 log10 copies/ml, respectively. The plasma viral load decreased by a median of 1.20 log10 copies/ml and the CD4 cell count increased by a median 60 x 10(6) cells/l at week 24 of therapy. Seventy-one per cent of the patients achieved a plasma viral load < 500 copies/ml and 45% achieved a viral load < 50 copies/ml. Patients exhibiting phenotypic resistance to saquinavir at baseline experienced a median decrease in HIV RNA of 0.91 log10 copies/ml at week 24 of therapy, as compared with a decrease of 1.52 log10 copies/ml in those exhibiting sensitive viral strains (P = 0.03). Genotypic resistance to saquinavir was not predictive of virologic failure. CONCLUSION: Our results indicate that the combination of ritonavir, saquinavir and efavirenz is safe and effective at 24 weeks in over two-thirds of patients who previously failed on highly active antiretroviral therapy, and that the determination of phenotypic resistance may be of greater value than the detection of resistance mutations to predict the outcome of salvage therapy in this setting.

Adult↗
PubMed1999

Kinetics of antiviral activity and intracellular pharmacokinetics of human immunodeficiency virus type 1 protease inhibitors in tissue culture.

We have examined the kinetics of the inhibition of human immunodeficiency virus type 1 (HIV-1) particle infectivity by protease inhibitors (PIs) in cell culture, using either transfected HeLa cells or infected peripheral blood mononuclear cells (PBMCs) as producers of infectious virions. Both the kinetics of the initiation of antiviral activity after addition of the PIs to these cultures and the kinetics of restoration of virion infectivity after removal of the PIs from the treated cultures were examined. We found that the kinetics of initiation of particle infectivity inhibition produced by a high extracellular concentration (5 microM) of the inhibitors were similar for all five inhibitors tested: loss of particle infectivity was perceptible as early as 1 h after the initiation of PI treatment and increased gradually thereafter. By contrast, the durability of this antiviral effect following removal of the drug from the culture varied dramatically according to the drug studied. In transfected HeLa cells, saquinavir and nelfinavir exerted the most prolonged inhibition, with the half-lives of their antiviral activities being greater than 24 h, while ritonavir exerted an intermediate length of inhibition (18 h) and indinavir and amprenavir exerted a reproducibly shorter length of inhibition (5 h). For all five tested PIs, these kinetics were significantly faster in PBMCs than in HeLa cells. The striking differences in antiviral kinetics observed among the different PIs appear mostly due to differences in their intracellular concentrations and/or rates of cellular clearance. Our observations, although limited to tissue culture conditions, may help delineate the cellular parameters of the antiviral activities of HIV-1 PIs and further optimize the efficiencies of these antiretrovirals in vivo.

Antiviral Agents↗