A combination of two nucleoside analogues is currently the core of any antiretroviral regimen for HIV-1 infection. Stavudine plus lamivudine has shown an additive effect in vitro, as well as an ...absence of overlapping toxicity and cross-resistance.
To evaluate the antiviral efficacy of stavudine plus lamivudine in treatment-naive patients and in patients previously treated with other nucleoside reverse transcriptase inhibitors.
Prospective, open-label pilot study.
Three urban clinical centers in Paris.
83 patients with CD4+ cell counts between 50 and 400 cells/mm3 (42 treatment-naive and 41 treatment-experienced patients).
Stavudine, 40 mg twice daily (30 mg twice daily in patients with a body weight < or = 60 kg), and lamivudine, 150 mg twice daily.
Primary end points for efficacy included changes in plasma viral load and CD4+ cell count at 24 weeks compared with baseline.
Therapy with stavudine plus lamivudine resulted in a median decrease of 1.66 log10 (10(1.66)) (range, -3.04 to -0.79 log10) in plasma HIV-1 RNA; the median increase in CD4+ cell count was 108 cells/mm3 (range, -58 to 406 cells/mm3) at week 24 in treatment-naive patients. In treatment-experienced patients, the median reduction in plasma HIV-1 RNA was 0.55 log10 (range, -2.86 to 0.52 log10), and the median increase in CD4+ cell count was 46 cells/mm3 (range, -188 to 311 cells/mm3). The percentages of patients with less than 3000 HIV-1 RNA copies/mL and less than 400 copies/mL at 24 weeks were, respectively, 57% (95% CI, 41% to 72%) and 26% (CI, 12% to 40%) among treatment-naive patients and 22% (CI, 10% to 38%) and 5% (CI, 1% to 17%) among treatment-experienced patients. Of 82 patients, 14 (17%) experienced grade 3 or 4 toxicity and 2 discontinued therapy because of intolerance toward treatment.
Stavudine plus lamivudine seems to have a potent antiviral effect in treatment-naive and treatment-experienced patients. No major drug-limiting toxicity was found. This two-nucleoside combination should be considered in multidrug therapy for HIV.
We describe an HIV-infected man with recurrence of a toxoplasmic manifestation, despite immune reconstitution during highly active antiretroviral therapy. This atypical recurrence was more likely to ...be a reinfection than a reactivation, as attested by the genotypic analysis of the Toxoplasma gondii strain recovered from the patient.
Trecovirsen, a 25‐mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV‐positive volunteers as an IV infusion. Single doses ranged from 0.1 ...to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmacokinetic parameters could be assessed at doses ≥0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half‐life increased and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, transitory increase in activated partial thromboplastin time at doses ≥ 2.0 mg/kg that was related to plasma trecovirsen concentrations and is attributed to the polyanionic character of the molecule. Thus, trecovirsen administration was well tolerated in single IV doses up to 2.5 mg/kg.
Les traitements antirétroviraux Katlama, Christine; Tubiana, Roland
Annales de l'Institut Pasteur. Actualités,
7/2000, Letnik:
11, Številka:
3
Journal Article
Recenzirano
Les acquis récents en matière de thérapeutique antirétrovirale ont bouleversé favorablement le pronostic et le cours de la maladie a VlH. Ainsi, des associations thérapeutiques comportant deux ...analogues nucléosidiques et un inhibiteur de la protéase, communément déanommées trithérapies ont, en permettant une réduction profonde de la charge virale et une augmentation des lymphocytes CD4, conduit à la réduction de 80 % de la mortalité, et de 85 % des infections opportunistes
15, 25, 36, 40.
Ainsi, ces données, s'il en était besoin, permettaient de valider une fois de plus le lien de causalité nette entre CD4, charge virale et maladie clinique.
La mise à disposition quasi généralisée en France au printemps 1996, de la mesure de la charge virale allait permettre au clinicien thérapeute d'apprécier « en directl'impact du traitement qu'il prescrivait, lui permettant de mesurer dans le même temps combien les monothérapies ou bithérapies pouvaient s'être révélées délétères en réduisant la charge virale de façon incomplète et transitoire, donnant alors toute liberté au virus de se répliquer en présence de molécules antivirales, et donc, de ce fait, de devenir résistant par mutation.
Cette inhibition puissante de la réplication du VIH chez les premiers patients recevant une combinaison thérapeutique triple composée d'un inhibiteur de la protéase (IP) et de deux analogues nucléosidiques inhibiteurs de la transcriptase inverse (NRTI,
nuclosidic reverse trancriptase inhibitor) avait autorisé l'espoir d'obtenir chez les patients « répondeurs— ayant une charge virale indétectable dans le sang périphérique — une éradication du VIH. La mise en évidence par plusieurs équipes de la presence de cellules infectées de façon latente et contenant l'ADN proviral du VIH ainsi que la possibilité d'une réplication continue à bas bruit chez des patients parfaitement contrôlés sous traitement ont tempéré ces objectifs
17, 51.
La raise en évidence de la résistance du VIH aux différentes molécules qui lui sont opposées ne fut pas une surprise. Cependant, cette réalité devient inquiétante si l'on considère que la charge virale reste détectable chez 40 % des patients bénéficiant d'un traitement antirétroviral, et que le nombre de patients en échec thérapeutique tend à augmenter avec le temps
11.
À l'aube de l'an 2000, d'autres défis sont lancés aux thérapeutes du VIH et à la recherche clinique.
a) La tolérance des traitement s'amenuise avec le temps ; apparaissent des effets secondaires sévères tels que le syndrome de lipodystrophie ou les modifications du métabolisme glucido-lipidique qui peuvent, à terme, compromettre certains traitements si aucune solution n'est envisagée.
b) En l'absence d'éradication, la thérapeutique devra être maintenue pendant des années. La toxicité au long cours des traitements, la lassitude des patients envers ceux-ci, nous imposent de réfléchir à d'autres voies thérapeutiques : recherche de molécules agissant sur d'autres cibles du cycle du rétrovirus, immunothérapie avec, en particulier, pour objectif la recherche d'une immunisation spécifique contre le VIH permettant d'envisager peut-être la suspension des traitements.
Fozivudine tidoxil (FZD) is a thioether lipid-zidovudine (ZDV) conjugate with anti-HIV activity demonstrated in vitro and in pilot phase I studies. To assess its safety, efficacy and ...pharmacokinetics, we conducted a multicenter, randomized, double-blind, placebo-controlled trial of FZD monotherapy in 72 HIV-infected patients who had not previously received antiretroviral therapy. In each dosage group (200 mg daily, 400 mg daily, 200 mg twice daily, 800 mg daily, 400 mg twice daily, and 600 mg twice daily), 12 patients were randomized to receive in a 10:2 ratio either FZD or a placebo for 4 weeks. Overall, FZD was well tolerated in all dosage groups; only 1 patient discontinued the drug, because of a moderate rise in aminotransaminase activity. HIV viral load fell in all the patients who were receiving FZD, except in the 200 mg daily group. The largest decrease (-0.67 log10) was observed in the 600 mg twice daily group. The plasma half-life was significantly longer (approximately 3.8 hours) than that of the parent drug ZDV. Exposure to ZDV, as reflected by the area under the time-concentration curve, was much lower after FZD than after ZDV administration. FZD thus appears to be as effective as and potentially better tolerated than ZDV during short-term administration and has the advantage of once daily intake.
To assess the effect of interleukin (IL)-2 combined with highly active antiretroviral therapy (HAART) on HIV-1 pro-viral DNA quantification in HIV-1-infected patients with CD4<200/mm3.
Seventy ...patients with CD4<200 cells/mm3 and CV<1000 copies/ml were enrolled in a 6-month randomized controlled study to evaluate the subcutaneous injection of IL-2 in addition to HAART versus HAART alone. Then, in a non-comparative phase from week 28 to week 80, IL-2 was proposed to patients from both groups. The HIV-1 pro-viral DNA was quantified at baseline, week 24 and week 50 by a real-time polymerase chain reaction (PCR) assay in peripheral blood mononuclear cells (PBMC). Analysis of resistance mutations was performed at baseline and after 6-months of IL-2.
HIV-1 DNA level in PBMC increased significantly in patients treated with 6 months of HAART combined to IL-2 (+0.24 log10, P=0.009) compared to a slight decrease in patients treated with HAART alone (-0.05 log10). Moreover, a DNA increase was observed in control group patients when receiving 6 months of IL-2 (+0.34 log10). No increase of HIV-1 DNA was seen when this measure was expressed per million CD4 cells; it was probably hidden by the intense increase of CD4 lymphocytes after 6 months of IL-2 administration. No evolution of resistance mutations in pro-viral DNA was observed during 6 months of IL-2, despite the increase of pro-viral DNA and the occurrence of transient increase of viraemia.
Administration of IL-2 combined with HAART in HIV-1 infected-patients with advanced disease led to an increase of HIV-1 pro-viral DNA per million PBMC without virological failure or emergence of resistance.
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