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Anne-Geneviève Marcelin

Publications and source records attributed to Anne-Geneviève Marcelin.

At least 19 recordsLinked to original sources
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↗
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

Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial.

BACKGROUND: The antiviral efficacy of didanosine in patients experiencing virological failure is not well known. METHODS: A total of 168 patients (139 men and 29 women) receiving stable antiretroviral therapy with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL were randomly assigned to have didanosine (n=111) or placebo (n=57) added to their currently failing regimen for 4 weeks. The primary efficacy end point was the change in HIV-1 RNA level from baseline to week 4. RESULTS: At baseline, the median HIV-1 RNA level was 3.8 log(10) copies/mL, the median CD4 cell count was 378 cells/mm(3), and the median number of nucleoside reverse-transcriptase inhibitor-associated mutations (NAMs) was 4. At week 4, a significant decrease in the median HIV-1 RNA level was observed in the didanosine group, compared with that in the placebo group (-0.56 vs. +0.07 log(10) copies/mL, respectively) (P<.0001). A total of 33 patients (31%) in the didanosine group, compared with 3 (6%) in the placebo group, had HIV-1 RNA levels <400 copies/mL (P<.001). Significant antiviral activity of didanosine was observed in patients with up to 5 NAMs at baseline. Diarrhea occurred in 5 patients (5%) in the didanosine group and 2 patients (4%) in the placebo group. CONCLUSIONS: In HIV-1-infected patients experiencing failure of antiretroviral therapy, didanosine retains short-term antiviral activity.

Adult↗
PubMed2005

Salivary lactoferrin is recognized by the human herpesvirus-8.

Human herpesvirus-8 (HHV-8) is commonly detected in all epidemiologic forms of Kaposi's sarcoma. Despite the broad cellular tropism of HHV-8, studies on mucosal shedding of HHV-8 have shown that infectious particles are restricted to saliva isolated from the oropharynx. We used biotinylated purified HHV-8 particles in a direct binding assay to whole clarified human salivary samples isolated from HHV-8-infected and uninfected individuals. We found that the major binding activity was carried out by a protein of 78-kDa size, which was further characterized as human lactoferrin (hLf) using 2-D electrophoresis and MALDI-ToF analysis. Preliminary comparison of HHV-8 binding activity of 76 salivary samples from HHV-8-infected and uninfected individuals showed that 7.8% of the uninfected population exhibited a form of Lf not recognized by HHV-8. Deglycosylation of hLf by PNGase F did not reduce HHV-8 binding activity, whereas endoproteinase cleavage of native hLf generated a non-glycosylated 8-kDa peptide recognized by HHV-8 particles and was located at the position Ala606-Tyr679 in the native hLf amino acid sequence, corresponding to the C-terminal region of the glycoprotein. This work identify the lactoferrin in saliva as a ligand for HHV-8 and suggests that this glycoprotein could be used as a carrier for the viral particles.

Adult↗
PubMed2005

Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitor-experienced patients.

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of -1.50 log(10) copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C(min) concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.

Adult↗
PubMed2005

Clinically relevant genotype interpretation of resistance to didanosine.

We analyzed the didanosine (ddI) arm of the randomized, placebo-controlled Jaguar trial in order to define a genotypic score for ddI associated with virologic response. In this arm, 111 patients experiencing virologic failure received ddI in addition to their current combination therapy for 4 weeks. The impact of mutations in the reverse transcriptase gene on the virologic response to ddI was studied in univariate analysis. Genotypic score was constructed using step-by-step analyses first including only mutations associated to poorer virologic response (scored as +1), while secondarily, mutations associated to a better response (scored as -1) were also eligible. Eight mutations were associated with a reduced response to ddI, M41L, D67N, T69D, L74V, V118I, L210W, T215Y/F, and K219Q/E, and two mutations were associated with a better response, K70R and M184V/I. The best prediction of the virologic response to ddI was obtained with a composite score comprising mutations added and subtracted (set II, M41L + T69D + L74V+ T215Y/F + K219Q/E - K70R - M184V/I; P = 4.5 x 10(-9)) and by comparing that to only mutations added (set I, M41L + T69D + L74V + L210W + T215Y/F + K219Q/E; P = 1.2 x 10(-7)). Patients had a human immunodeficiency virus RNA reduction of 1.24, 0.84, 0.61, 0.40, and 0.07 log(10) copies/ml when they were ranked as having a genotypic score II of -2, -1, or 0 or 1 and 2 mutations or more, respectively. In conclusion, we developed and validated a genotypic score, taking into account mutations negatively and positively impacting the virologic response to ddI.

Adult↗
PubMed2005

Comparison of tests and procedures to build clinically relevant genotypic scores: application to the Jaguar study.

OBJECTIVE: To compare non-parametric tests and procedures of selection in building clinically validated genotypic scores. DESIGN AND PATIENTS: In the Jaguar study, 111 patients on a stable antiretroviral regimen experiencing virological failure were randomized in the didanosine (ddI) arm to receive ddI for 4 weeks in addition to their current combination therapy. METHODS: The virological response was HIV-1 RNA reduction from baseline to week 4. The univariate impact of each mutation associated with resistance to ddI on virological response was quantified by comparing reduction in plasma HIV-1 RNA in patients with or without the specific mutation, using a Wilcoxon-Mann-Whitney test. The next step was to select the combination of mutations most strongly associated with the virological response. Two procedures and two tests were compared using either the set of resistance mutations or the set of resistance mutations and mutations providing a better virological response. The Kruskal-Wallis and the Jonckheere test for ordered alternatives were compared in order to build a genotypic score using the two distinct procedures. RESULTS: Eight mutations were associated with a reduced virological response to ddI: M41L, D67N, T69D, L74V, V1181, L210W, T215Y/F and K219Q/E and two mutations with a better virological response: K70R and M184V/I. The Jonckheere-Terpstra test for trend provided the combination of mutations (M41L+T69D-K70R+L74V-M184V /I+T215Y/F+ K219A/E) that were the most predictive for the week 4 virological response, that is, leading to the lowest P value. The 'removing' procedure, starting from a set of mutations retained and removing mutations one by one to find the best combination, provides lower P values than the 'adding' procedure starting with a single mutation and adding mutations one by one. Whatever the set of mutations and the procedure used, the Jonckheere-Terpstra test selects combinations of mutations leading to lower P values than the Kruskal-Wallis test. CONCLUSION: The Jonckheere-Terpstra test for trend is recommended for building a genotypic score when compared with the Kruskal-Wallis. The choice of the selection procedure is discussed here and may be dependent on the objective of the score.

Anti-HIV Agents↗
PubMed2004

Characterization of genotypic determinants in HR-1 and HR-2 gp41 domains in individuals with persistent HIV viraemia under T-20.

We analysed the genetic changes in gp41 in a population of 30 heavily pretreated HIV-1-infected patients failing on a T-20-containing salvage therapy. This study confirms the key role of the number of drugs presumed to be still effective associated with T-20 in the magnitude of the virological response. Our results suggest that only HR-1 sequencing is necessary to characterize resistance to T-20, and that HR-2 domain sequencing is probably not required.

Drug Resistance, Viral↗
PubMed2004

Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure.

During ZDV or d4T exposure, mutations at codons 41, 67, 70, 210, 215, and 219 can be selected and were named thymidine analogue mutations (TAMs). Some previous results suggested that different TAMs patterns could exist and that the kind of TAMs pattern could influence the virological response to some nucleoside reverse transcriptase inhibitors (NRTIs). In order to get more data about the relative prevalence of these patterns, their associations with other NRTI resistance mutations and the identification of the different stages observed during the acquisition of TAMs under treatment by NRTIs, we collected 1,098 RT sequences harbouring at least one TAM from patients failing to antiretroviral regimen. Sequences were stored in a database designed specifically to allow the retrieval of sequences that met specific criteria such as the occurrence and frequency of a particular mutation, the nature and frequency of the amino acid substitution at a given codon, and/or the rate of association between resistance mutations. Two pathways of TAMs can be identified: profile #1 (T215Y mutation linked) and profile # 2 (T215F mutation linked). The frequency of selection of profile # 1 is two times higher than profile # 2. The E44D/A + V118I complex, 69 insertions, and L74V mutation are associated to profile #1, whereas the Q151M complex and M184V mutation are associated to both profiles. As some NRTI resistance mutations were associated preferentially with profile #1, further studies are needed to explore if, the weaker efficacy observed on viruses harbouring this profile using some NRTIs, could be explained by the TAMs profile itself or the other associated NRTI resistance mutations.

Anti-HIV Agents↗
PubMed2004

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients.

Amprenavir (APV) is an HIV protease inhibitor (PI) used for the treatment of either naive or PI-experienced HIV-infected patients. Several genotypic resistance pathways in protease gene have been described to be associated to unboosted APV failure (I50V, V32I + I47V, I54L/M, or less commonly I84V, which may be accompanied by one ore more accessory mutations such as L10F, L33F, M46I/L). The aims of this study were to investigate the efficacy up to week 24 of an APV plus ritonavir containing regimen in PI experienced patients and to determine the genotypic resistance profiles emerging in patients failing to this therapy. Forty-nine, PI experienced but APV naïve patients were treated with APV (600 mg bid) plus ritonavir (100 mg bid). By intent-to-treat analysis, the median decrease in viral load (VL) was -1.32 log10 (min +0.6; max -2.8) and -1.46 log10 (min +0.5; max -2.8) 12 and 24 weeks after initiating APV plus ritonavir regimen, respectively. Twelve patients harboured a VL >200 copies/ml at week 24. Among these patients, the selection of mutations previously described with the use of APV as first PI (V32I, L33F, M46I/L, I50V, 54M/L, and I84V) was observed. However, in some cases, mutations classically described after the use of other PIs (V82F and L90M) were selected but always with APV-specific mutations. There was no relation between the resistance pathways selected with either APV or ritonavir plasma minimal concentration, but higher APV plasma minimal concentration were associated with a lower rate of resistance mutations selection.

Adult↗
PubMed2004

Fatal disseminated Kaposi's sarcoma following human herpesvirus 8 primary infections in liver-transplant recipients.

Human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS) and rare lymphoproliferative disorders in immunosuppressed patients. The risk of HHV-8 transmission by liver transplantation and the clinical manifestations of primary infection in this setting have yet to be determined. In order to evaluate this risk, we measured the seroprevalence of HHV-8 among 122 liver donors and their respective recipients before and after transplantation. Molecular methods and immunohistochemical analyses were performed to study the features of HHV-8 infection. Antibodies to HHV-8 were detected in sera of 4 donors before transplantation (3.3%) and of 3 recipients (2.4%). None of the 3 recipients, who were HHV-8 seropositive before transplantation, developed a KS during the follow-up. Four primary HHV-8 infections were detected among the 4 HHV-8 seronegative recipients who received a liver from an HHV-8 positive donor. Among these 4 recipients, 2 particularly immunosuppressed patients developed symptomatic diseases and died a few months after transplantation, harboring disseminated KS and HHV-8 positive lymphoproliferation. In these 2 patients, HHV-8 DNA genome sequences were detectable in peripheral blood mononuclear cells and other tissues with high viremia levels before and at the beginning of HHV-8-related diseases. In conclusion, in liver transplantation recipients, HHV-8 primary infection can be associated with fatal outcome. This study raises the question of screening liver donors for HHV-8--even in low HHV-8 infection prevalence countries--not systematically to exclude the graft but to monitor, clinically and biologically, patients who received a graft from an HHV-8-infected donor.

Adolescent↗
PubMed2004

Quantification of Kaposi's sarcoma-associated herpesvirus in blood, oral mucosa, and saliva in patients with Kaposi's sarcoma.

The aims of this study were to measure Kaposi's sarcoma-associated herpesvirus (KSHV) load in oral mucosa and blood and to determine their relationship with clinical activity of KS in both AIDS-Kaposi's sarcoma (KS) and HIV-unrelated KS patients. Among AIDS patients, KSHV viral load in peripheral blood mononuclear cells (PBMCs) was higher in patients with active KS than in patients with KS in complete remission. In HIV-unrelated KS patients, KSHV viral load in PBMCs was not correlated with clinical stage. Thus, monitoring KSHV viral load in PBMCs could be useful, particularly in the context of HIV infection. In patients with HIV-unrelated KS, KSHV viral load in oral compartments can be very high even in patients with nonactive KS, implying that patients with nonactive KS are still a potential source of transmission of KSHV through oral contact.

Acquired Immunodeficiency Syndrome↗