Donna Mildvan

The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double blind, placebo-controlled trial

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.

Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1

Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1–infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-α (IFN-α) in response to HIV-1–encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably 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 may 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 new approach to reduce HIV-1–associated pathology.

Opportunistic infections and immune deficiency in homosexual men.

A syndrome of opportunistic infections and acquired immune deficiency occurred among four previously healthy homosexual men. Fever, leukopenia, and diminished delayed hypersensitivity were accompanied by various degrees of proctitis, perianal ulcerations, and lymphadenopathy. The infectious agents included Pneumocystis carinii, Cryptococcus neoformans, Candida albicans, herpes simplex virus, and cytomegalovirus. The immune deficiency was characterized as a persistent and profound selective decrease in the function as well as number of T lymphocytes of the helper/inducer subset and a possible activation of the suppressor/cytotoxic subset. Three patients died despite aggressive anti-infective therapy.

Central-Nervous-System Toxoplasmosis in Homosexual Men and Parenteral Drug Abusers

Central-nervous-system toxoplasmosis developed in 7 of 269 patients with the acquired immunodeficiency syndrome reported to the New York City Health Department through July 1982. Focal neurologic abnormalities, mass lesions on computed-tomographic brain scans, lymphocytic cerebrospinal fluid pleocytosis, and detectable IgG antibody to Toxoplasma gondii were common; but IgG titers of 1:1024 or more, IgM antibody to T. gondii, and positive open brain biopsies were uncommon. Serologic findings suggested that the disease resulted from recrudescent rather than primary infection. Four of five patients improved when treated with sulfonamides and pyrimethamine, but 2 had relapses. An aggressive diagnostic approach and sometimes even empiric therapy are warranted when central-nervous-system toxoplasmosis is suspected in a seropositive patient with the acquired immunodeficiency syndrome.

HIV Incidence Among Injection Drug Users in New York City, 1990 to 2002: Use of Serologic Test Algorithm to Assess Expansion of HIV Prevention Services

OBJECTIVES We sought to estimate HIV incidence among injection drug users (IDUs) in New York City from 1990 to 2002 to assess the impact of an expansion of syringe exchange services. Syringe exchange increased greatly during this period, from 250,000 to 3,000,000 syringes exchanged annually. METHODS Serum samples were obtained from serial cross-sectional surveys of 3,651 IDUs. HIV-positive samples were tested with the Serologic Test Algorithm for Recent HIV Seroconversion (STARHS) assay to identify recent HIV infections and to estimate HIV incidence. Consistency with other incidence studies was used to assess strengths and limitations of STARHS. RESULTS HIV incidence declined from 3.55/100 person-years at risk (PYAR) from 1990-1992, to 2.63/100 PYAR from 1993-1995, to 1.05/100 PYAR from 1996-1998, and to 0.77/100 PYAR from 1999-2002 (P<.001). There was a very strong negative linear relationship (r= -.99, P<.005) between the annual numbers of syringes exchanged and estimated HIV incidence. These results were highly consistent with a large number of shorter incidence studies among IDUs conducted during the time period. CONCLUSIONS STARHS testing of samples from large serial cross-sectional surveys can provide important data for the assessment of community-level HIV prevention.

Reductions in hepatitis C virus and HIV infections among injecting drug users in New York City, 1990-2001

Objective:To assess trends in HIV, hepatitis C virus (HCV) and HIV/HCV infection among injecting drug users (IDU) from 1990 to 2001 in New York City. The 1990–2001 time period included a very large expansion of syringe exchange in New York City, from 250 000 to 3 000 000 syringes exchanged annually. Methods:Cross-sectional seroprevalence surveys of IDU entering drug abuse treatment in New York City, with sample sizes for HCV of 72 in 1990–1991 and 412 in 2000–2001. A structured risk behavior questionnaire was administered, and HIV and HCV testing were conducted. HCV testing was performed on de-linked stored serum samples. Results:Over the 1990–2001 period, HIV prevalence declined from 54 to 13%. HCV prevalence declined from 80 to 59% among HIV-seronegative individuals, and from 90 to 63% overall. The estimated HCV incidence in 2000–2001 among new injectors was 18 per 100 person-years at risk. Conclusions:The large-scale expansion of syringe exchange was temporally associated with large reductions in both HIV and HCV prevalence. The prevalence and incidence of HCV, however, still remain at high levels among IDU in New York City.

Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus

Ganciclovir is a congener of acyclovir with in vitro activity against cytomegalovirus. Ninety-seven patients with the acquired immune deficiency syndrome (AIDS) and a serious cytomegalovirus infection received ganciclovir, 3.0 to 15 mg/kg per day. Viremia cleared during drug therapy in 88 percent of patients. Viral shedding from urine and throat ceased or became inapparent during treatment in 78 percent and 68 percent of patients, respectively. Among patients with cytomegalovirus retinitis, 87 percent of evaluable patients had improvement in (30 of 60) or stabilization (22 of 60) of their disease. However, when the drug was discontinued, progression or recurrence of disease always occurred. Long-term suppressive therapy with ganciclovir, 5.0 mg/kg five to seven times weekly, prevented the recurrence of cytomegalovirus disease (p less than 0.001). The drug was eliminated by renal excretion, and in patients without renal impairment (creatinine clearance rates of more than 60 ml/minute/1.73 m2), ganciclovir has a mean half-life of 4.2 hours. Significant neutropenia and leukopenia occurred in 55 percent and 32 percent of patients, respectively.

INFECTION OF CHIMPANZEES BY HUMAN T-LYMPHOTROPIC RETROVIRUSES IN BRAIN AND OTHER TISSUES FROM AIDS PATIENTS

The authors report the isolation of acquired immunodeficiency syndrome (AIDS) associated retroviruses from packed leukocytes of 2 chimpanzees inoculated intracerebrally and intravenously with brain tissue suspension from 2 patients with AIDS encephalopathy on days 7 and 14 after inoculation. Antibody to the AIDS-associated retroviruses has appeared in sera of 2 chimpanzees inoculated intravenously with plasma from different AIDS patients in 1 chimpanzee inoculated intravenously with brain and thymus suspension and in 1 chimpanzee inoculated intracerebrally with brain tissue suspension from a patient with AIDS encephalopathy. 11 chimpanzees inoculated with supernatant fluids from tissue cultures infected with human T-lymphotropic virus type III (HTLV-III) lymphadenopathy-associated virus (LAV) and IDAV have acquired antibodies to the LAV/HTLV-III viral antigens 2-8 weeks after inoculation. Virus was recovered from the lymphocytes of all 6 seroconverted animals between 8-154 days after primary inoculation of HTLV-III. 2 animals have severe suppression of T-cell function. However all 23 chimpanzees that have seroconverted to HTLV-III or LAV antigen have remained clinically well for 2-15 months of follow-up. There have been no tumors lymphadenopathy or severe opportunistuc infections. Other species of non-human primates similarly inoculated with HTLV-III and LAV have not seroconverted 2-10 months postinoculation. These findings confirm the active and persistent virus infection of chimpanzees with retroviruses derived from AIDS patients. They further establish the presence of viruses in the plasma and brain of AIDS patients by direct transmission of their virus to chimpanzees.

Anemia in HIV Infection: Clinical Impact and Evidence-Based Management Strategies

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.

Once-Daily versus Twice-Daily Lopinavir/Ritonavir in Antiretroviral-Naive HIV-Positive Patients: A 48-Week Randomized Clinical Trial

The safety, pharmacokinetics, and antiviral activity of lopinavir, a human immunodeficiency virus (HIV) protease inhibitor, coformulated with ritonavir as a pharmacokinetic enhancer were evaluated in 38 antiretroviral-naive patients randomized 1:1 to receive open-label lopinavir/ritonavir at a dose of 800/200 mg once daily or 400/100 mg twice daily, each in combination with stavudine and lamivudine twice daily, for 48 weeks. Over the course of 48 weeks, median predose concentrations of lopinavir exceeded the protein-binding corrected concentration required to inhibit replication of wild-type HIV by 50% in vitro by 40- and 84-fold in the once- and twice-daily groups, respectively. Predose concentrations of lopinavir were more variable in the once-daily group (mean +/- SD, 3.62+/-3.38 microg/mL for the once-daily group and 7.13+/-2.93 microg/mL for the twice-daily group). At week 48, in an intent-to-treat (missing = failure) analysis, 74% of patients in the once-daily group and 79% of patients in the twice-daily group had HIV RNA levels of <50 copies/mL (P=.70). Study drug-related discontinuations occurred in 1 patient in each treatment group. Genotypic resistance testing of 4 patients with HIV RNA levels >400 copies/mL between weeks 24 and 48 demonstrated no protease inhibitor-resistance mutations.