Gag mutations can impact virological response to dual-boosted protease inhibitor combinations in antiretroviral-naïve HIV-infected patients.

ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P = 0.04) and 449 (p1/p6(gag)) (P = 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6(pol)) was associated with virological response (P = 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patients.

We report the long-term outcome of 27 HIV-infected patients treated for over 3 years with IL-2 and binucleoside analogues. These patients experienced a sustained increase in CD4 cells and a decrease of proviral DNA with infrequent IL-2 cycles. In three cases, virus could not be isolated from activated peripheral cells. A high frequency of HIV-1-specific memory CD4 T cells was found in the patients studied. IL-2 maintains specific effector cells and reduces the pool of infected cells in patients, albeit treated only with binucleosides.

Acute activation of CD8+ T lymphocytes in interleukin-2-treated HIV-infected patients. ANRS-048 IL-2 Study Group. Agence Nationale de Recherches sur le SIDA.

CD8+ T lymphocytes play a key role in the control of HIV infection, through both cytotoxic and noncytotoxic mechanisms. To study in vivo effects of interleukin-2 (IL-2) treatment on this cell compartment, the level of activation of CD8+ T lymphocytes was evaluated before and just after 5-day administration of IL-2 in 16 HIV-infected patients. The serum level of soluble CD25 and of soluble CD8 significantly increased following IL-2 administration. The number of mRNA molecules coding for perforin and granzyme B, two enzymes that are contained in granules of cytotoxic cells, also significantly increased in peripheral blood mononuclear cells and in purified CD8+ cells (p < .001). Variations of plasma HIV viremia and perforin gene expression following IL-2 administration were inversely correlated (p = .023), suggesting that IL-2-induced activation of CD8+ T lymphocytes contributes to limit HIV replication in vivo. In contrast to perforin and granzyme B gene expression, IL-2 administration did not increase the expression of macrophage inhibitory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated-on-activation normal T-expressed and secreted (RANTES) genes. These findings indicate that CD8+ T lymphocytes in HIV-infected patients are acutely activated by IL-2 treatment, which may improve long-term control of HIV infection.

Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.

BACKGROUND: Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients. METHODS: 94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56. FINDINGS: CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p<0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups. INTERPRETATION: Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial.

The efficacy of low-dose aspirin in preventing fetal growth retardation was tested in a randomised, placebo-controlled, double-blind trial. A secondary aim was to find out whether dipyridamole improves the efficacy of aspirin. 323 women at 15-18 weeks' amenorrhoea were selected at twenty-five participating centres on the basis of fetal growth retardation and/or fetal death or abruptio placentae in at least one previous pregnancy. They were randomly allocated to groups receiving placebo, 150 mg/day aspirin, or 150 mg/day aspirin plus 225 mg/day dipyridamole, for the remainder of the pregnancy. In the first phase of the trial all actively treated patients (n = 156) were compared with the placebo group (n = 73). Mean birthweight was significantly higher in the treated than in the placebo group (2751 [SD 670] vs 2526 [848] g; difference 225 g [95% CI 129-321 g], p = 0.029) and the frequency of fetal growth retardation in the placebo group was twice that in the treated group (19 [26%] vs 20 [13%]; p less than 0.02). The frequencies of stillbirth (4 [5%] vs 2 [1%]) and abruptio placentae (6 [8%] vs 7 [5%]) were also higher in the placebo than in the treated group. The benefits of aspirin treatment were greater in patients with two or more previous poor outcomes than in those with only one. In the second analysis, of aspirin only (n = 127) vs aspirin plus dipyridamole (n = 119), no significant differences were found. There was no excess of maternal or neonatal side-effects in the aspirin-treated patients.