We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.

Manifestations of viral infections can differ between women and men 1 , and significant sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral load levels early in HIV-1 infection, but progress faster to AIDS for a given viral load than men 2-7 . Here we demonstrate substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce significantly more interferon-α (IFN-α) in response to HIV-1-encoded TLR7 ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naïve chronically HIV-1-infected women had significantly higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs can account for higher immune activation in women compared to men at a given HIV-1 viral load, and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a novel approach to reduce HIV-1-associated pathology. According to UNAIDS, almost half of all HIV-1-infected individuals worldwide are women. Studies comparing the course of HIV-1 infection between women and men have demonstrated significant sex differences in the manifestations of HIV-1 disease. While HIV-1-infected women present with lower viral load early in HIV-1 infection, women with the same HIV-1 viral load as men have a 1.6-fold higher risk of developing AIDS 2-7 . The mechanisms underlying these significant sex differences in the manifestation of HIV-1 disease are not understood. NIH Public AccessThere is increasing consensus that the level of immune activation in HIV-1-infected subjects is a strong independent predictor for HIV-1 disease progression [8][9][10][11][12][13][14][15][16] . Plasmacytoid dendritic cells (pDCs) play a central role in this HIV-1-induced activation of the immune system, as they can sense HIV-1 ssRNA via Toll-like receptor (TLR)7 [17][18][19][20] . Interestingly, PBMCs derived from women have been shown to produce significantly more IFN-α in response to the synthetic TLR7 ligand Imiquimod than PBMCs derived from men 21 . We therefore reasoned that sex differences in HIV-1-induced immune activation might be responsible for the observed differences in HIV-1 disease, and investigated differences in cytokine production by PBMC in response to HIV-1 between men and women, and their consequences for T cell activation.Intracellular cytokine staining (ICS) using multiparameter flow cytometry was performed to quantify the percentage of pDCs producing IFN-α or TNF-α after stimulation with HIV-1-derived TLR7/8 ligands, TLR9 ligand ODN2216 (CpG-A), or inactivated HIV-1 virus (AT-2 virus) (Fig. 1). A significantly higher percentage of pDCs derived from women produced IFN-α in response to HIV-1-derived TLR ligands or AT-2 viru...

We conducted a double-blind, placebo-controlled trial of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Although significant clinical benefit was documented (N Engl J Med 1987; 317:185-91), serious adverse reactions, particularly bone marrow suppression, were observed. Nausea, myalgia, insomnia, and severe headaches were reported more frequently by recipients of AZT; macrocytosis developed within weeks in most of the AZT group. Anemia with hemoglobin levels below 7.5 g per deciliter developed in 24 percent of AZT recipients and 4 percent of placebo recipients (P less than 0.001). Twenty-one percent of AZT recipients and 4 percent of placebo recipients required multiple red-cell transfusions (P less than 0.001). Neutropenia (less than 500 cells per cubic millimeter) occurred in 16 percent of AZT recipients, as compared with 2 percent of placebo recipients (P less than 0.001). Subjects who entered the study with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects. Concurrent use of acetaminophen was also associated with a higher frequency of hematologic toxicity. Although a subset of patients tolerated AZT for an extended period with few toxic effects, the drug should be administered with caution because of its toxicity and the limited experience with it to date.

Anemia in human immunodeficiency virus (HIV)-infected patients can have serious implications, which vary from functional and quality-of-life decrements to an association with disease progression and decreased survival. In 2002, 16 members of the Anemia in HIV Working Group, an expert panel of physicians involved in the care of HIV-infected patients that met first in 1998, reconvened to assess new data and to translate these data into evidence-based treatment guidelines. The group reached consensus on the prevalence of anemia in the highly active antiretroviral therapy era; the risk factors that are independently associated with the development of anemia; the impact of anemia on quality of life, physical functioning, and survival; the impact of the treatment of hepatitis C virus coinfection on anemia in HIV-infected patients; evidence-based guidelines for treatment of anemia in HIV-infected patients, including the therapeutic role of epoetin alfa; and directions for future research.

Thomas Campbell and colleagues report findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing.