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Vincent Calvez

Publications and source records attributed to Vincent Calvez.

At least 19 recordsLinked to original sources
PubMed2007

The origins of concentric demyelination: self-organization in the human brain.

Baló's concentric sclerosis is a rare atypical form of multiple sclerosis characterized by striking concentric demyelination patterns. We propose a robust mathematical model for Baló's sclerosis, sharing common molecular and cellular mechanisms with multiple sclerosis. A reconsideration of the analogies between Baló's sclerosis and the Liesegang periodic precipitation phenomenon led us to propose a chemotactic cellular model for this disease. Rings of demyelination appear as a result of self-organization processes, and closely mimic Baló lesions. According to our results, homogeneous and concentric demyelinations may be two different macroscopic outcomes of a single fundamental immune disorder. Furthermore, in chemotactic models, cellular aggressivity appears to play a central role in pattern formation.

Brain↗
PubMed2007

Efficacy and safety of tenofovir double-dose in treatment-experienced HIV-infected patients: the TENOPLUS study.

Drug resistance is an increasing problem in the treatment of HIV infection. Tenofovir has been shown to inhibit HIV replication even with thymidine-associated resistance mutations (TAMs) if they are limited to two or less. Double-dose of tenofovir disoproxil fumarate (TDF) (600 mg QD) was used to determine weather the drug could be virologically effective in patients harbouring HIV-strains resistant to nucleoside analogues (NRTI). A pilot, open, non-comparative add-on study, where patients failing a current antiretroviral regimen, with at least two TAMs, and naive for tenofovir, were given tenofovir 600 mg once-daily for 4 weeks, in addition to their current failing antiretroviral regimen. The primary end-point was the percentage of patients with plasma viral load (VL) reduction of at least 0.8 log(10) between baseline and week 4 (W4). Ten patients were enrolled. At baseline, the median viral load was 3.66 log(10) copies/ml (range 3.13-4.03) and the median CD4 cell count was 407/mm(3) (range 136-1102). The percentage of patients with reduction the viral load > or =0.8 log(10) was 40% at W4. After 4 weeks of treatment with tenofovir 600 mg, the median decrease in the viral load was -0.61 log(10) (range -0.05; -0.88) and the median gain of CD4 was +109/mm(3). Despite a twofold increase tenofovir plasma concentrations, no serious drug-related adverse event were recorded except for one patient experiencing an de Fanconi syndrome at week 2. This add-on pilot study supports the concept of double dose tenofovir to virologically overcome the decreased sensitivity of NRTI-resistant viruses. However, the safety of this regimen needs to be considered carefully.

Adenine↗
PubMed2006

Phenotypic susceptibility to didanosine is associated with antiviral activity in treatment-experienced patients with HIV-1 infection.

OBJECTIVE: We investigated the relationship between human immunodeficiency virus (HIV) phenotypic susceptibility to didanosine and the antiviral activity of didanosine (ddI) in the JAGUAR study. METHODS: Baseline plasma HIV phenotypic susceptibility to ddI was assessed using a phenotype assay of patients randomized to receive ddI or placebo for 4 weeks in addition to their current regimen. Phenotypic susceptibility scores (PSSs) were then calculated for each sample. Associations between PSS and week 4 reductions in plasma HIV-1 RNA load or virologic response were assessed using linear regression and Jonckherre's test and the Wilcoxon and Cochran-Armitage tests, respectively. RESULTS: In the ddI arm, a significant association between reduction in viral load and continuous PSS was observed (P<.0001). Using distinct categories, an increasing fold change (FC) in susceptibility to ddI was strongly associated with smaller reductions in plasma HIV-1 RNA load (P<.0001). The proportion of virologic responders was 83% (15/18) for patients with a ddI FC < or =1.3, 50% (33/66) for patients with an FC of 1.3-2.2, and 29% (4/14) for patients with an FC > or =2.2 (P=.0008). After we determined these findings, 3 ddI FC categories were defined using 1.3 and 2.2 as thresholds. CONCLUSIONS: The relationship between phenotypic susceptibility to ddI and reduction in plasma HIV-1 RNA load describes a continuum. The establishment of a lower clinical cutoff at 1.3 and an upper clinical cutoff at 2.2 are clinically relevant.

Anti-HIV Agents↗
PubMed2006

Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients.

OBJECTIVES: The sequence variability in the protease and in the 5 Gag cleavage sites (CS) were explored to look for eventual associations between the mutations. Moreover, we have evaluated associations between the Gag region sequence and the virological response to Protease Inhibitors (PI). METHODS: The protease and the 5 Gag CS sequences from 98 PI-experienced patients were sequenced and compared to the HXB2 reference sequence. Sixty patients, treated by Saquinavir plus Ritonavir, were studied to evaluate the clinical impact of the Gag region variability. RESULTS: The relationship between 63 protease mutations and 21 Gag CS mutations were explored. Two patterns of mutations in the protease were identified: (M46I/L, I54V, V82A/T/F) was associated to the A431V and (K20I/R/M, L89M/I) to the S373Q and L449P. None of the Gag CS mutations resulting from PI treatment was associated to the virological response to SQV/r. On the other hand, the S373P mutation had a negative impact on the virological response that remained statistically significant in a multivariate analysis after adjustment on the number of PI resistance mutations. CONCLUSIONS: These results evoke the pertinence to introduce some mutations found in the Gag CS in the algorithms used for the interpretation of resistance testing.

Amino Acid Sequence↗
PubMed2006

[HIV drug resistance].

HIV drug resistance can be defined as any change (in protease, reverse transcriptase gene or envelope protein) that improves viral replication in the presence of an inhibitor. One of the most important causes of treatment failure is the development of resistance to antiretrovirals by HIV. Resistance studies have highlighted distinct evolution patterns of mutations and cross resistance among drug classes, which have the ability to impact on the choice of subsequent salvage treatment. A number of resistance testing technologies have been developed to measure HIV drug resistance and prospective studies have shown that the use of these resistance tests have the ability to improve the virological response to a salvage regimen. These tests are now widely used in developed countries and are recommended in case of therapeutic failure in treated patients and in case of recent infection in naive patients.

Anti-Retroviral Agents↗
PubMed2006

Role of HIV-1 minority populations on resistance mutational pattern evolution and susceptibility to protease inhibitors.

We investigated, in the protease and GAG cleavage sites, the role of minority populations on the evolution of resistance to a subsequent boosted protease inhibitor (PI) regimen after a first failure to nelfinavir. Two pathways were observed: the addition of mutations to a currently dominant genotype when minority variants are not shown, or the emergence of a minority variant as a dominant strain. These minor species, not detected by standard genotype, may influence PI susceptibility.

Drug Resistance, Multiple, Viral↗
PubMed2006

Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients.

OBJECTIVE: To develop a clinically relevant genotypic resistance score for boosted atazanavir (ATV) in protease inhibitor-experienced patients. METHODS: At baseline, 62 patients with HIV-1 RNA > 1000 copies/ml switched to a boosted ATV regimen (300 mg ATV, 100 mg ritonavir once daily); two were excluded from analysis at 3 months as they had undetectable plasma ATV. The impact of baseline protease mutations on virological response (> 1 log10 copies/ml plasma HIV RNA decrease) at 3 months was analysed using Fisher's exact test. Mutations with prevalence > 8% and P < 0.2 were retained. Cochran-Armitage's test was used to select the combination of mutations most strongly associated with reduced virological response. Robustness of the score was investigated using bootstrap resampling. RESULTS: At 3 months, 82% of patients had a virological response and 56% had RNA < 50 copies/ml. Eight mutations (10F/I/V, 16E, 33I/F/V, 46I/L, 60E, 84V, 85V and 90M) were retained in the genotypic resistance score (P = 8.67 x 10) and virological response was observed in 100%, 100%, 80%, 42%, and 0% of patients with none, one, two, three, and four/five mutations, respectively. There was 100% response in patients with a score < 2 independently of the number of active drugs, whereas in patients with a score > or = 3 there was a gradient of response according to the number of active drugs (0%, 29% and 60% with none, one and two/three active drugs, respectively). CONCLUSIONS: The occurrence of three of the eight mutations in the ATV/RTV genotypic resistance score predicted a clinically identifiable reduced response in patients.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Repeated HIV-1 resistance genotyping external quality assessments improve virology laboratory performance.

The performance of French virology laboratories belonging to the ANRS network has been assessed annually for 3 years. The performance of these laboratories was compared between the years 2002 and 2003. Ten and 7 coded samples were sent to 38 virology laboratories in 2002 and 45 virology laboratories in 2003, respectively. Each panel of coded samples included at least one HIV-negative control, a pair of duplicate specimens, samples with a wide range of viral loads, and samples with a large number of resistance mutations. The laboratories used their standard sequencing procedures and were asked to report the amino acids at codons associated with resistance mutations, based on the IAS-USA expert panel list. The reference amino acid sequences were defined as those most frequently reported by the participants. The specificity of detection of RT mutations was significantly better in 2003 (99.9%) than in 2002 (99.7%) (P = 0.05). There was no difference between 2002 and 2003 in the specificity of detection of protease mutations (99.6% and 99.8%) or the sensitivity of detection of RT mutations (98.8% and 98.2%). The sensitivity of detection of protease mutations improved significantly between 2002 and 2003 (97.6% and 99.0%, respectively; P = 0.037). The proportion of laboratories reporting fully accurate results, in terms of amplification, specificity, sensitivity, and reproducibility, tended to increase between 2002 and 2003 (P = 0.077). No errors were made by 19% of laboratories in 2002, compared to 42% in 2003. These results show the value of repeated external quality assessments.

Clinical Laboratory Techniques↗
PubMed2006

Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial.

BACKGROUND: Ritonavir (RTV)-boosted atazanavir (ATV) and tenofovir disoproxil fumarate (TDF-DF) are promising in highly experienced patients because of their pharmacokinetic profile, activity, safety and resistance properties. METHODS: A 26-week study of the safety and efficacy of RTV-boosted ATV plus TDF-DF was conducted in 53 HIV-infected patients who were failing their current highly active antiretroviral therapy (HAART) regimen. Patients with history of failure to at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) were randomized to either continue their current regimen (group 1) or replace the PI by ATV (300 mg once daily) boosted by RTV (100 mg; group 2) for 2 weeks. Then, all patients received the same combination of ATV, RTV and TDF-DF (300 mg) plus optimized NRTIs regimen. RESULTS: At baseline, median CD4+ T-cell count was 206/mm3, median viral load (VL) 5.0 log10/ml and median numbers of NRTI, NNRTI and PI resistance mutations were 7, 1 and 8, respectively. At week 2, median VL remained unchanged from baseline in group 2 as compared with group 1 (-0.1 vs -0.1 log10/ml). At week 26, a mild decrease in median VL from baseline of 0.2 log10/ml was observed, with 16 (31%) and 9 (17%) patients exhibiting a decrease in viral load of at least 0.5 and 1.0 log10/ml, respectively. Baseline phenotypic and genotypic resistance to ATV were the most predictive independent factors of virological response. The regimen was well tolerated. CONCLUSION: In these very advanced patients failing highly HAART, the combination of boosted ATV plus TDF-DF yielded low antiretroviral activity.

Adenine↗
PubMed2006

Foscarnet salvage therapy for patients with late-stage HIV disease and multiple drug resistance.

OBJECTIVE: To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. METHODS: Three drugs experienced patients with plasma viral load (pVL) > 50,000 copies/ml and CD4+ T-cell counts < 100/mm3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log10 decrease in pVL at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6. RESULTS: Eleven patients were enrolled with a median baseline pVL at 5.16 log10 copies/ml, median CD4+ T-cell count at 10/mm3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intent-to-treat analysis, the median change in pVL from baseline was -1.99 log10 copies/ml at W2 and -1.79 log10 copies/ml at W6. Eight out of eleven patients had a fall in pVL of at least 1 log10 at W6, and six started maintenance therapy. The median fall in pVL after 12 weeks of maintenance therapy was -0.85 log10 copies/ml in the four patients who reached W12, and the median increase of CD4+ T-cell count was 60/mm3. CONCLUSION: In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status.

Adult↗
PubMed2005

No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients.

OBJECTIVE: To evaluate the potential benefits of a tailored antiretroviral treatment interruption with duration based on the observed reversion of resistance mutations. METHODS: In this open single-arm pilot study, 23 patients with multiple treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log10 copies/ml after 12 weeks of salvage therapy. RESULTS: Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 10 cells/l. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of treatment interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log10 copies/ml and -30 x 10(6) cells/l. At the end of treatment interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load > 1 log copies/ml. All baseline resistance mutations recurred after treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period. CONCLUSION: In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.

Anti-HIV Agents↗
PubMed2005

Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1.

BACKGROUND/AIMS: Adefovir dipivoxil (10 mg once-daily) was added to antiretroviral therapy including lamivudine in 35 HIV/HBV co-infected patients. METHODS: Parameters evaluated included alanine aminotransferase (ALT), HBV DNA and serological markers, HIV-1 RNA, and CD4+ cell count. RESULTS: Twenty-nine patients (83%) completed 144 weeks. Serum HBV DNA declined from a baseline 9.76 log10 copies/mL (median) to 4.68, 5.24, and 5.90 log10 copies/mL at weeks 48, 96, and 144, respectively (P<0.0001 at all time points). Seven patients (25%) achieved HBV DNA<2.3 log10 copies/mL. No adefovir-associated resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were detected. ALT declined from 81 IU/L (median) at baseline by -16.0, -44.5, and -46.0 IU/L at week 48, 96 and 144, respectively (P=<0.05, respectively), and normalized in 71% of patients (20 of 28) by week 144. Two patients developed antibodies against HB 'e' antigen by week 48. No serious adverse events related to adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable. CONCLUSIONS: Treatment with adefovir dipivoxil for 144 weeks was well tolerated and resulted in significant and sustained reductions in HBV DNA and ALT in HIV/HBV co-infected patients. Efficacy increased with treatment duration, with no loss of viral suppression.

AIDS-Related Opportunistic Infections↗
PubMed2005

Therapeutic immunization with a human immunodeficiency virus (HIV) type 1-recombinant canarypox vaccine in chronically HIV-infected patients: The Vacciter Study (ANRS 094).

This open single-arm study evaluated whether the administration of an HIV-recombinant canarypox vaccine (vCP1433) in highly active antiretroviral therapy (HAART)-treated patients chronically infected with HIV was safe, immunogenic and associated with prolongation of treatment discontinuation: 48 patients received four monthly vCP1433 injections and stopped HAART. Immunization was safe. HIV-p24-specific lymphoproliferative responses (LPR), significantly increased in the whole group after two injections but decreased thereafter, HIV-gag-specific CD8 T cells were boosted in 55% patients tested. Altogether, 11% patients with at least one HIV-specific LPR during immunization remained off therapy after 44 weeks of interruption. Detection of such LPR response at the time of treatment interruption was significantly associated with the probability of remaining off therapy. These results provide rationale for future randomized trials exploring this strategy.

AIDS Vaccines↗
PubMed2005

HIV-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen.

BACKGROUND: It has been demonstrated that, in patients treated by protease-inhibitor-based regimen, intermittent viraemia occurred frequently and was associated with higher concentrations of residual replication but not with virological failure. Risk factors associated with intermittent viraemia and its impact in patients treated by non-nucleoside-reverse-transcriptase-inhibitor-based (NNRTI) regimen need to be evaluated. METHODS: We analyzed the occurrence of blips (one HIV-1 RNA > 50 copies/ml with a subsequent value < 50 copies/ml), the level of these blips (between 3 and 50 copies/ml) and their effect on CD4 cell count and the occurrence of virological failure in 43 patients with stable suppression of HIV-1 plasma viraemia (< 50 copies/ml) under NNRTI-based therapy. RESULTS: Eight out of 43 patients had one episode of blips during the follow-up (median = 350 copies/ml). Comparing patients with and without blips, the median level of HIV-1 RNA at baseline was 7.5 versus 3 copies/ml (P = 0.008), respectively. Patients with blips had a significantly lower CD4 cell count after 12 and 18 months than the others. Plasma concentrations of NNRTI before, during, and after the blips were adequate. In addition, the occurrence of blips was not associated with virological failure. CONCLUSION: These results suggest that blips may reflect ongoing viraemia of below 50 copies/ml and can impair the CD4 cell count recovery under an NNRTI regimen. The impairment of CD4 cell count recovery seems to be affected more by the occurrence of blips than by the level of viraemia (< 50 copies/ml) itself. Nevertheless, despite a tight genetic barrier for resistance with NNRTI drugs, no virologic failure occurred during the follow-up.

Adult↗
PubMed2005

Clonal analyses of HIV quasispecies in patients harbouring plasma genotype with K65R mutation associated with thymidine analogue mutations or L74V substitution.

We analysed the quasispecies at a clonal level in patients whose plasma genotypic test harboured K65R with L74V or thymidine analogue mutations (TAM). We showed that the K65R and TAM such as M41L, D67N, T215Y/D, L210W and K219E can be borne by the same virus. We found no clone bearing both K65R and L74V substitutions. Moreover, the S68G and V75I mutations are not necessarily linked with K65R, and could thus have their own resistance effect.

Amino Acid Substitution↗