Biomedical subjects

Françoise Brun-Vezinet

Publications and source records attributed to Françoise Brun-Vezinet.

10 recordsLinked to original sources

PubMed2006

Proliferative, IFNgamma and IL-2-producing T-cell responses to HIV-2 in untreated HIV-2 infection.

OBJECTIVE: To evaluate HIV-2-specific proliferative, interferon (IFN)gamma- and interleukin (IL)-2-producing T-cell responses in HIV-2 infection and their relationship with plasma HIV-2 RNA. METHODS: HIV-2-Gag-p26 and cytomegalovirus (CMV)-specific CD4 T-cell responses from 19 untreated HIV-2-infected subjects (median CD4 cell counts, 561 x 10/l) were compared by lymphoproliferation assay, IFNgamma secretion in culture supernatants by ELISA, and intracellular staining (ICS) of IFNgamma and IL-2. CD8 responses were assessed by IFNgamma-ELISpot using pools of SIVmac239-Gag peptides (87% of homology with HIV-2). RESULTS: HIV-2-specific IFNgamma production was detected in 53% and 92% patients by ELISA and ICS, respectively, while HIV-2-specific IL-2 production was detected in only 33% by ICS and lymphoproliferation in 21% patients. All IL-2-producing CD4 T cells co-produced IFNgamma. Overall, frequencies of Th1 responses to HIV-2 were similar to CMV in subjects with undetectable plasma HIV-2 RNA, while significantly lower than CMV in HIV-2 RNA-positive subjects, despite similar CD4 cell counts in both groups. In addition, proliferative responses to HIV-2 were correlated to IFNgamma secretion (r > 0.68, P < 0.01), and were significantly higher in HIV-2 RNA-negative (P < 0.05) than in HIV-2 RNA-positive subjects. Frequencies of SIV-Gag-specific CD8 cells, detected in 93% of patients, were also higher in HIV-2 RNA-negative subjects, though not significantly. Overall, HIV-2-specific T-cell responses were not correlated to CD4 cell counts. CONCLUSION: Proliferative, IFNgamma- and IL-2-producing T-cell responses to HIV-2 are as robust as CMV-specific responses in untreated HIV-2 subjects with undetectable plasma HIV-2 levels, independently of CD4 cell depletion and despite lower frequencies of IL-2-producing T cells compared to IFNgamma. In addition, lymphoproliferative responses to HIV-2 were associated with lack of viral replication.

Adult↗

PubMed2005

French national sentinel survey of antiretroviral drug resistance in patients with HIV-1 primary infection and in antiretroviral-naive chronically infected patients in 2001-2002.

OBJECTIVE: To survey the frequency of genotypic antiretroviral resistance and the spread of non-B subtypes in patients with primary HIV-1 infection (2001-2002) and in treatment-naive chronically HIV-1-infected patients (2001). METHODS: Plasma samples from 303 patients with acute HIV-1 infection (Primo study) and 363 treatment-naive patients with chronic HIV-1 infection (Odyssee study) were tested for genotypic resistance. Resistance mutations were identified from the International AIDS Society Resistance Testing-USA panel and resistant viruses were defined according to the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm. RESULTS: In the Primo study, 14% of the patients had viruses with resistance mutations and 12% of patients had viruses with mutations conferring resistance to least 1 antiretroviral drug. Thirty patients had viruses with mutations to at least 1 antiretroviral drug in a single pharmacologic class. Six patients were infected by viruses resistant to 2 or 3 classes of drugs. In the Odyssee study, the prevalence of reverse transcript (RT) associated and major protease inhibitor-associated mutations was 6.1% (95% CI: 3.6-8.6). Six patients had viruses resistant to at least 1 antiretroviral drug and 3 patients had viruses resistant to 2 classes of antiretroviral drugs. Twenty-four percent of acutely infected patients harbored non-B subtype strains (19% in 1999-2000) and 33.2% of chronically infected patients (10% in 1998; P < 0.0001). CONCLUSION: In France, the frequency of HIV-1 resistance in untreated patients was not significantly higher in 2001-2002 than in previous surveys while the prevalence of non-B subtypes is increasing.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs.

We studied the evolution of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations among 29 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced virologic failure when receiving an NNRTI-containing regimen (nevirapine, delavirdine, or efavirenz) and subsequently switched to antiretroviral therapy without NNRTIs. Genotypic resistance was determined from plasma samples collected at the time of NNRTI withdrawal (baseline) and during follow-up. At baseline, 83% of patients had more than two thymidine analog resistance mutations (TAMs), and all had NNRTI resistance mutations. Mutations at codons 103, 181, and 190 were found in 62, 62, and 34% of the patients, respectively. Follow-up samples were available after a median time of 6 months in all patients and at 12 months in 22 patients. The mean number of resistance mutations to NNRTIs was significantly lower at months 6 (1.34 +/- 1.04) and 12 (1.18 +/- 1.05) than at month 0 (2.03 +/- 1.02) (P < 0.009). The percentages of patients with at least one NNRTI resistance mutation were 100, 76, and 73% at baseline, month 6, and month 12, respectively (P < 0.0044). Overall, 70% of the patients had a mutation at codon 103 or 181 at month 12. The mean number of TAMs did not vary significantly during follow-up. Our data show that, in the context of maintained antiretroviral therapy, NNRTI resistance mutations persist in two-thirds of the patients in spite of NNRTI withdrawal. These results argue for the low impact of NNRTI resistance mutations on viral fitness and suggest that resistance mutations to different classes of drugs are associated on the same genome, at least in some of the resistant strains.

Antiretroviral Therapy, Highly Active↗

PubMed2004

Once-daily dosing of saquinavir soft-gel capsules and ritonavir combination in HIV-1-infected patients (IMEA015 study).

This was a prospective pilot study evaluating a saquinavir (SQV) soft-gel capsules (SGC)/ritonavir (RTV)-containing once-daily regimen over a follow-up of 3 months. The primary end-point was to determine the number of patients both remaining on treatment at month 3 and with trough SQV plasma concentration 24 h after the last intake (C24h) exceeding the inhibition of 95% of viral replication in vitro (IC95). The secondary end-points were to investigate the immuno-virological efficacy and safety of SQV-SGC/RTV once daily, and to explore SQV concentrations in peripheral blood mononuclear cells (PBMCs). Twenty-three antiretroviral-naive and 17 protease inhibitors (PIs) experienced HIV-1-infected patients with plasma HIV-1 RNA level below 200 copies/ml were enrolled. They were assigned to SQV-SGC/RTV (1600/100 mg once daily) combined with nucleoside and/or non-nucleoside reverse transcriptase inhibitors. In a subgroup of 13 patients, both plasma and intracellular SQV concentrations were determined. By intent to treat analysis the percentage of success at month 3 was 87.5% (confidence interval: 73.2-95.8%) with 78.3% in naive and 100% in PI-experienced patients. SQV C24h and intracellular concentrations [median (range, n)] were 241 ng/ml (40-1209, 35) and 323 ng/ml (168-475, 12), respectively. Intracellular concentrations showed an accumulation of SQV in PBMCs persisting during 24 h. Neither immunological nor virological failure was observed. Clinical and biological tolerance was acceptable in all patients but three with adverse effects leading to discontinuation. These data confirmed the short-term efficacy of SQV-SGC/RTV once-daily regimen based on SQV therapeutic drug monitoring.

Adult↗

PubMed2003

Factors associated with clinical progression in HIV-2 infected-patients: the French ANRS cohort.

OBJECTIVES: To identify factors associated with clinical progression in HIV-2 infected patients. DESIGN: French prospective cohort initiated in 1994. METHODS: Follow-up data are collected twice a year; viral load is assessed once a year by cellular viraemia, quantitative proviral DNA and plasma RNA. A Cox proportional-hazards model was used for studying baseline factors associated with clinical progression. RESULTS: By December 2001, 217 patients had been enrolled. At inclusion, 80%, 6% and 14% were Centers for Disease Control and Prevention (CDC) group A, B and C, respectively. Median CD4 cell count was 436 x 10(6)/l. In the 48% of positive specimens, the median plasma RNA titre was 3.0 log10 copies/ml. Mean follow-up of the 179 patients seen at least twice was 34.4 months. Of these 13 died and nine progressed to group C. Ninety-three (52%) received antiretroviral therapy during a mean of 33 months, including a protease inhibitor in 48%. The probability of remaining AIDS-free was 97% and 95% at 1 and 3 years, respectively. Independent variables associated with clinical progression were age > or = 40 years [hazard ratio (HR), 11; 95% confidence interval (CI), 1.4-91.8; P = 0.03] and plasma RNA (HR, 2.5 per additional log10 copies/ml; 95% CI, 1.3-4.7, P < 0.01). Prior group B symptoms and CD4 cell count < 200 x 10(6)/l were associated with progression to AIDS. AIDS and plasma RNA were predictive of death. CONCLUSION: Considering the limited progression rate of HIV-2 infection, combined antiretroviral therapy should be discussed in patients with high plasma RNA titres, which threshold value remains to be defined. It is recommended in case of AIDS, CDC group B symptoms or CD4 cell count < 200 x 10(6)/l.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Stable prevalence of genotypic drug resistance mutations but increase in non-B virus among patients with primary HIV-1 infection in France.

OBJECTIVE: To evaluate the frequency of drug-resistant HIV-1 viral strains from patients presenting with primary infection in 1999-2000 and to survey the molecular epidemiology of these viruses circulating in France. METHODS: Resistance mutations were detected by sequencing the reverse transcriptase and the protease genes in plasma samples from 249 individuals. Phylogenetic analysis was performed on the reverse transcriptase genes. RESULTS: Ten per cent of patients [26/249; 95% confidence interval (CI) 7-15%] presented with virus mutations associated with resistance to at least one antiretroviral drug. The distribution of the resistance mutations was as follows: to nucleoside reverse transcriptase inhibitors in 19 (8%; 95% CI 5-12%) and to non-nucleoside reverse transcriptase inhibitors in 10 (4%; 95% CI 2-7%). Primary resistance mutations to protease inhibitors were detected in 14 (6%; 95% CI 3-9%). Twelve patients (5%; 95% CI 3-8%) presented with virus harbouring mutations associated with resistance to two or three classes of antiretroviral drugs. The median HIV RNA in plasma at enrollment was lower in patients with one or more drug resistance mutations than in patients with no mutations (5.05 log versus 5.47 log, P = 0.05). Phylogenetic analysis revealed that 19% (14-24%) of patients harboured HIV-1 non-B subtype strains; this proportion remained high when Caucasian patients only were considered (14%). CONCLUSION: This study, performed within the French network on HIV-1 primary infection survey, revealed no change in the frequency of resistant viral strains over time, but showed an increasing prevalence of non-B subtypes overall and among Caucasian individuals.

Drug Resistance, Viral↗

PubMed2003

Safety of cryopreservation straws for human gametes or embryos: a study with human immunodeficiency virus-1 under cryopreservation conditions.

BACKGROUND: The possibility of assisted reproductive technology (ART) for couples carrying viruses, especially HIV-1, necessitates consideration of the safety of cryopreserving human gametes or embryos in liquid nitrogen tanks. Following our evaluation of the safety of three kinds of straws containing HIV-1 at 37 degrees C, we have now examined the HIV-1 imperviousness of the same straws under cryopreservation conditions. METHODS: Polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG) and high-security ionomeric resin (IR) straws (24 each) were tested. Each straw was filled with 100 microl of HIV-1-containing supernatant [reverse transcriptase (RT) activity: 15 000 c.p.m./50 microl]. Then PVC and PETG straws were sealed ultrasonically only at their free-end, and IR straws were thermosoldered at both ends. Each straw was put in a 15 ml Falcon tube which was capped and submerged in a liquid-nitrogen tank for 7 days. After bleach decontamination or not, the outside of each end of the straw was rinsed with RPMI medium (1 ml) before cryopreservation and after thawing. Viral RNA was extracted from the medium and then amplified by RT-polymerase chain reaction (PCR) followed by nested-PCR using HIV-1 protease-specific primers. RESULTS: HIV-1 RNA was detected in some PVC and PETG rinse media, probably resulting from splashing during ultrasonic sealing, but not in the rinse media of thermosoldered IR straws. CONCLUSION: Under cryopreservation conditions, IR straws would appear to be safe for HIV-1 storage in ART. For PVC and PETG straws, as highlighted in this study, the ultrasonic sealing could be the weak safety link.

Composite Resins↗

PubMed2003

Triple nucleoside combination zidovudine/lamivudine/abacavir versus zidovudine/lamivudine/nelfinavir as first-line therapy in HIV-1-infected adults: a randomized trial.

OBJECTIVE: To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patients. DESIGN: Open-label study in HIV-1-infected ART-naive adults, randomized to receive either Combivir (lamivudine 150 mg/zidovudine 300 mg twice daily) + abacavir (300 mg twice daily), or Combivir + nelfinavir (750 mg every 8 h) for 48 weeks. Plasma HIV-1 RNA, CD4 cell count and adverse events were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48. RESULTS: 195 subjects (131 men, 64 women), median age 34 years, were randomized: 98 received combivir/abacavir and 97 combivir/nelfinavir. Baseline median plasma HIV-1 RNA was 4.2 log10 copies/ml [Interquartile range (IQR): 3.7-4.5.2] and 4.1 log10 copies/ml (IQR: 3.8-4.6), respectively. Baseline median CD4 cell count was 387 cells/mm3 (IQR: 194-501) and 449 cells/mm3 (IQR: 334-605), respectively. Nine patients (3 vs 6, respectively) did not start treatment or did not have any available efficacy data. At week 48, using the intent to treat analysis (switch/missing equals failure), plasma HIV-1 RNA was <50 copies/ml in 54/95 (57%) and 53/91 (58%) of subjects, respectively. Median CD4 increase was +110 and +120 cells/mm3, respectively. Possible hypersensitivity reactions to abacavir were reported in four subjects (4%). CONCLUSION: The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults, with comparable antiviral activity to a nelfinavir-containing regimen at week 48.

Adolescent↗

PubMed2002

Relationship between exposure to zidovudine and decrease of P24 antigenemia in HIV-infected patients in monotherapy.

The link between virological response and exposure to zidovudine was studied in 40 HIV-infected patients of the protocol ANRS 01. During this 45-day trial, the patients received only oral zidovudine in six treatment groups. Our objectives were: to analyze and model the pharmacokinetics of zidovudine and the decrease of P24 antigenemia; to study the links between exposure and efficacy. For the pharmacokinetic study, 12 blood samples were collected from 0.16 to 24 h after the first dose and a compartmental model was used. For the pharmacodynamic study of P24 antigenemia, blood samples were collected before treatment and every 3 days until day 45; an exponantial decay model was used. The pharmacokinetic and pharmacodynamic parameters were estimated for each patient by nonlinear regression. The correlations between efficacy parameters and exposure parameters, were then studied in the 40 patients. The mean (+/- SD) apparent volume of distribution and clearance were 151 L (+/- 94) and 184 L/h (+/- 72), respectively. The mean initial antigen level was 472 pg/mL (+/- 409), the coefficient of reduction of antigenemia was 0.27 (+/- 0.21) and the rate of decrease was 0.27/day (+/- 0.16). The coefficient of P24 reduction was found to be significantly correlated to the daily area under the curve (P < 0.0014). This relationship was adequately described by an Imax model and the daily area under the curve, leading to 50% of antigenemia decrease, was estimated to be 2.32 mg x h/L (+/- 0.33). In conclusion, a significant relationship between exposure to zidovudine at day 1, and decrease of P24 antigenemia was found. It was estimated that the average steady-state concentration, which corresponds to 70% of maximal efficacy, was 0.22 mg/L. Together with the large interpatient variability of zidovudine pharmacokinetics, these findings confirmed that zidovudine should be monitored and a clinical target concentration was defined.

AIDS-Related Complex↗

PubMed2002

Efficacy of zidovudine compared to stavudine, both in combination with lamivudine and indinavir, in human immunodeficiency virus-infected nucleoside-experienced patients with no prior exposure to lamivudine, stavudine, or protease inhibitors (novavir trial).

We compared the efficacy and the toxicity of zidovudine (AZT) versus stavudine (d4T), in combination with lamivudine (3TC) and indinavir, in AZT-, dideoxyinosine (ddI)-, and/or dideoxycytosine (ddC)-experienced patients in a randomized comparative multicenter trial. One hundred seventy human immunodeficiency virus type 1 (HIV-1)-infected patients, who had received AZT, ddI, and/or ddC for at least 6 months but were naive for d4T, 3TC, and protease inhibitors, were randomized to AZT at 250 to 300 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h or to d4T at 40 mg twice daily, 3TC at 150 mg twice daily, and indinavir at 800 mg every 8 h. The primary endpoint was time to virological failure, defined as plasma HIV-1 RNA levels of >5,000 copies/ml after at least 8 weeks of antiretroviral therapy. Additional endpoints were change from baseline in CD4 cell counts, AIDS-defining events and adverse events, and proportion of patients with HIV-1 RNA levels of <500 copies/ml and HIV-1 RNA levels of <50 copies/ml. At week 80, 15 patients in the AZT arm and 14 patients in the d4T arm had reached the primary endpoint, and time to virological failure did not differ between the two arms (P = 0.98). In the d4T and in the AZT arms, 67 and 73% of patients, respectively, had HIV-1 RNA levels of <500 copies/ml (P = 0.50). The median change from baseline in CD4 cell count was 195 x 10(6) and 175 x 10(6)/liter for the d4T- and AZT-containing arms, respectively. The proportions of patients with HIV-1 RNA levels of <50 copies/ml at weeks 8, 16, and 24 were similar in the two arms. The occurrence of serious adverse events was not significantly different between arms. In conclusion, in these patients heavily pretreated with AZT, switching from AZT to d4T when initiating indinavir and 3TC did not bring any additional benefit compared to maintaining AZT.

Adult↗