Lymphoma and Epstein-Barr virus DNA in blood during interleukin-2 therapy in antiretroviral-naïve HIV-1-infected patients: a substudy of the ANRS 119 trial.

OBJECTIVES: Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein-Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. METHODS: A total of 130 ART-naïve patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL). RESULTS: Four lymphomas occurred, a median of 61 weeks [range 40-94 weeks] after randomization at a median CD4 cell count of 396 cells/µL (IQR 234-536 cells/µL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8). CONCLUSIONS: IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.

Evaluation of the interlaboratory concordance in quantification of human immunodeficiency virus-specific T cells with a gamma interferon enzyme-linked immunospot assay.

The gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay is a reference method for the ex vivo monitoring of antigen-specific T cells and a primary tool for assessing clinical trials of human immunodeficiency virus (HIV) or cancer vaccines. Four experienced laboratories in Paris compared their results with this method by exchanging frozen blood samples from eight HIV-seronegative and eight HIV-seropositive subjects. Each laboratory measured the IFN-gamma-producing cells specific for HIV, Epstein-Barr virus, cytomegalovirus, and influenza using the same set of peptides and the same ELISPOT reader but its own ELISPOT technique. The cutoff values for positive responses (50 or 100 spot-forming cells/10(6) peripheral blood mononuclear cells over background) were consistent with the binomial statistic criterion. The global qualitative concordance, as assessed by the kappa index, ranged from 0.38 to 0.92, that is, moderate to excellent, and was better for non-HIV 9-mer peptide pools than for HIV 15-mer peptide pools. The interlaboratory coefficient of variation for the frequency of virus-specific T cells was 18.7% (data are expressed on a log scale). Clustering analysis of HIV-positive subjects showed qualitative agreement for ELISPOT results from all four laboratories. Overall, the good interlaboratory qualitative concordance of IFN-gamma ELISPOT assays with only the peptide source and ELISPOT reader in common suggests that a qualitative comparison of interlaboratory findings is feasible. Nonetheless, a single set of standard operating procedures should be used in multicenter trials to improve standardization.

Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team).

CONTEXT: In the Trilège trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy. OBJECTIVE: To identify mechanisms of virologic failure in the 3 arms of the Trilège trial. DESIGN: Case-control study conducted from February to October 1998. SETTING: Three urban hospitals in Paris, France. PATIENTS: Fifty-eight case patients with virologic failure (HIV RNA rebound to >500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression. MAIN OUTCOME MEASURES: At virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods. RESULTS: Only 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms. CONCLUSIONS: During the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Randomized comparison of amphotericin B deoxycholate dissolved in dextrose or Intralipid for the treatment of AIDS-associated cryptococcal meningitis.

We conducted a randomized, open-labeled clinical trial to compare the tolerability and efficacy of amphotericin B deoxycholate, prepared in 5% dextrose or Intralipid (Kabi Pharmacia, Saint-Quentin-en-Yvelines, France), in the treatment of AIDS-associated cryptococcal meningitis in Burundi. Forty-four patients were assigned to receive amphotericin B/dextrose (0.7 mg/[kg.d]) for 14 days; the dose was then reduced to 1 mg/kg every other day for 28 days (infused over 6 hours). Forty-six patients were assigned to receive Intralipid/amphotericin B at a 50% higher dosage (1 mg/[kg.d]) for 14 days; the dose was then reduced to 1.5 mg/kg every other day for 28 days (infused over 2 hours). Intralipid significantly decreased the incidence of fever (P = .02) and chills (P = .0001) related to the infusion of amphotericin B deoxycholate. Analysis of the time to the onset of increased levels of serum creatinine (creatinine level, > 150 mumol/L) showed that Intralipid/amphotericin B was more nephrotoxic (P = .03). The percentage of patients who were clinically cured or had improvement in their conditions and successful mycological outcome was similar in both therapeutic groups, but analysis of the time to the first negative cerebrospinal fluid culture showed a nearly significant difference that favored Intralipid/amphotericin B (P = .07). Intralipid reduced the infusion-related toxicity of amphotericin B deoxycholate without altering its antifungal efficacy but did not confer substantial benefit against renal toxicity that would allow the unitary dosage of amphotericin B deoxycholate to be increased safely.

[Antiretroviral treatments in human immunodeficiency virus infection]. / Les traitements antirétroviraux dans l'infection par le virus de l'immunodéficience humaine (VIH).

Antiretroviral drugs already registered or currently in clinical trials are shortly described, including dideoxynucleosides, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, tat inhibitors and antisens molecules. In a second part, the treatment of patients with the nucleosides already on the market or in a pre-registration phase is reviewed, on the basis of an analysis of available phase III clinical trials. The third part describes the strategy of clinical trials and explains why "surrogate markers" including markers of viral replication cannot yet be the main criteria to evaluate the efficacy of a new drug in a phase III trial.