Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team.

OBJECTIVE: To prospectively examine differences in baseline characteristics and study outcomes between HIV-infected women and men during a clinical trial of nucleoside analogue therapy. METHODS: ACTG 175 randomized HIV-infected patients with CD4+ counts between 200 and 500 cells/mm3 to one of four nucleoside analogue regimens: zidovudine (ZDV), didanosine (ddI), ZDV + ddI, or ZDV + zalcitabine (ddC). Differences in time to first dose modification, voluntary withdrawal, development of toxicity and symptomatology, and AIDS progression were compared by gender. RESULTS: The study included 438 women and 2029 men. Baseline values of HIV RNA plasma concentrations were significantly lower for women (0.3 log10) than men in a subset of patients in whom assays were taken and this difference persisted after adjustment for CD4+ count. Women reported reducing dosage and discontinue ddI-containing regimens more frequently than men did; adjustment for weight did not completely explain this difference. Women were at lower risk than men for progression to a study endpoint (19% of women versus 24% of men; p <.0001). Among those antiretroviral-naive study subjects receiving ZDV, men were four times more likely to progress to a study endpoint than women. CONCLUSIONS: Differences in pretreatment characteristics and on study experiences were demonstrated between women and men enrolled in this clinical trial. The suggestion of a gender difference in response to ZDV monotherapy by antiretroviral-naive study subjects and the lower baseline values for HIV RNA in women compared with those in men provides evidence for gender differences in the relationship between virus replication, CD4+ decline, and responses to nucleoside analogue therapy.

Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection.

OBJECTIVE: To determine whether foscarnet has potential efficacy in the treatment of acyclovir-resistant mucocutaneous varicella-zoster infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-label study. SETTING: Three university medical centers. PATIENTS: Five patients with AIDS who were infected with thymidine-kinase-deficient or -altered strains of varicella-zoster virus. INTERVENTION: Foscarnet, 40 mg/kg body weight every 8 hours in 1-hour infusions for 10 or more days. MAIN RESULTS: Four patients had healing in response to foscarnet therapy, and each of four tested patients became culture negative for virus during foscarnet therapy. Results of fluorescent antigen testing remained positive during therapy in two patients; one of these patients had concomitant clinical failure but the other patient healed fully. One patient had complete healing despite the emergence of resistance to foscarnet in serial specimens obtained during foscarnet therapy. CONCLUSION: Foscarnet is a potentially effective and tolerable antiviral agent for patients with acyclovir-resistant, varicella-zoster virus infection; however, the optimal dosage and duration of therapy require further study, as does the relation between clinical findings and in-vitro susceptibility results.

HIV-infected health workers: how should we proceed?

Mandatory testing may seem to be a solution at first glance, but many thorny and problematic issues could arise in the long run. Instead, more emphasis needs to be placed on maintaining the highest standards of infection control practice.

Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone.

BACKGROUND: Antimicrobial drugs that can be taken orally are needed for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Preliminary data indicate that dapsone with trimethoprim may be an effective alternative to trimethoprim-sulfamethoxazole, which is frequently toxic. METHODS: In a double-blind trial, 60 patients with AIDS and mild-to-moderately-severe first episodes of P. carinii pneumonia (partial pressure of oxygen in arterial blood, greater than 60 mm Hg while breathing room air) were randomly assigned to 21 days of treatment with either trimethoprim-sulfamethoxazole (20 and 100 mg per kilogram of body weight per day, respectively) or trimethoprim-dapsone (20 mg per kilogram per day and 100 mg per day). RESULTS: The orally administered treatment failed because of progressive pneumonitis in 3 of the 30 patients assigned to trimethoprim-sulfamethoxazole and in 2 of the 30 assigned to trimethoprim-dapsone (P greater than 0.3). Major toxic effects required a switch to intravenous pentamidine for 17 patients (57 percent) in the trimethoprim-sulfamethoxazole group, as compared with 9 (30 percent) in the trimethoprim-dapsone group (P less than 0.025). With trimethoprim-sulfamethoxazole, there were more instances of severe chemical hepatitis (six, as compared with one in the trimethoprim-dapsone group) and marked neutropenia (five vs. one). Intolerable rash (three in each treatment group) and severe nausea and vomiting (two in each group) occurred with equal frequency with both drug combinations. Methemoglobinemia occurred in most of the patients treated with trimethoprim-dapsone, but it was asymptomatic and the level exceeded 20 percent in only one patient. Mild hyperkalemia (serum potassium level, 5.1 to 6.1 mmol per liter) also occurred in 53 percent of the patients treated with trimethoprim-dapsone. CONCLUSIONS: In patients with AIDS, oral therapy with trimethoprim-sulfamethoxazole and with trimethoprim-dapsone are equally effective for mild-to-moderate first episodes of P. carinii pneumonia, but with trimethoprim-dapsone there are fewer serious adverse reactions than with trimethoprim-sulfamethoxazole.

Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Evidence of drug interactions.

STUDY OBJECTIVE: To examine the interaction between dapsone and trimethoprim in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Measurement of drug levels as part of an open study of dapsone alone and randomized, double-blind comparison of trimethoprim-dapsone with trimethoprim-sulfamethoxazole in treating Pneumocystis carinii pneumonia in patients with AIDS. SETTING: County hospital and AIDS clinic. PATIENTS: Eighteen patients treated with dapsone alone, 30 with trimethoprim-dapsone, and 30 with trimethoprim-sulfamethoxazole. INTERVENTION: Dapsone, 100 mg/d; trimethoprim, 20 mg/kg body weight per day, and sulfamethoxazole, 100 mg/kg.d; administered for 21 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of dapsone were 40% higher in patients treated with trimethoprim-dapsone than in those treated with dapsone alone (2.1 compared with 1.5 micrograms/mL; P less than 0.05). Trimethoprimdapsone-treated patients had fewer treatment failures but more side effects and treatment terminations due to toxicity than those treated with dapsone alone. The concentration of trimethoprim was 48.4% higher in patients treated with trimethoprim-dapsone than in those treated with trimethoprim-sulfamethoxazole, (18.4 compared with 12.4 micrograms/mL; P less than 0.05). Discontinuation of therapy due to toxicity was commoner in the trimethoprim-sulfamethoxazole group (57% compared with 30%). CONCLUSIONS: A bidirectional drug interaction exists between dapsone and trimethoprim, resulting in higher concentrations of each in the presence of the other.

Women and the acquired immunodeficiency syndrome. An interview.

SPECIAL EDITOR'S NOTE: Constance B. Wofsy, MD, is Co-Director of AIDS Activities at San Francisco General Hospital and Medical Center, as well as Associate Clinical Professor of Medicine at the University of California, San Francisco; Assistant Chief, Infectious Diseases, San Francisco General Hospital; and Principal Investigator, Project AWARE (Association for Women's AIDS Research and Education). Although she was not able to contribute an article for WOMEN AND MEDICINE on this very important subject, she kindly agreed to an interview. Both physicians and nonphysicians were asked what questions they had about the acquired immunodeficiency syndrome (AIDS) and the human immunodeficiency virus (HIV) in women.

Prevention of HIV transmission.

With screening of the blood supply and effective heat and chemical treatment of blood product derivatives, the overwhelming majority of newly acquired adult HIV infections will result from consensual acts, through the exchange of blood or sexual secretions. Societal relaxation about discussion of sex, death, homosexuality, drugs, and abortion is essential to prevent further deaths. Careful partner selection, use of condoms in conjunction with nonoxynol-9 (a viricidal spermicide), and selected confidential HIV antibody testing could help decrease the number of infected persons. Efforts directed toward IV drug users to decrease initiation of drugs, make drug treatment more accessible, provide simple techniques for cleaning needles such as a quick rinsing with bleach and water, and emphasizing the risks of sharing needles could decrease the exponential rise of HIV infection in IV drug users. A substantial percentage of women infected with both HIV and hepatitis B are unaware of their infection. Information, counseling, and antibody testing of men and women prenatally with informed options could reduce infection in children. Health care providers must work through their own valid issues of fear and possible discomfort with various lifestyles to function effectively in the health professions.

AIDS care: providing care for the HIV infected.

To meet the needs of human immunodeficiency virus (HIV) infected individuals, innovative approaches to health care delivery have been developed that could affect the entire worldwide medical care system. Innovations include dedicated inpatient and outpatient AIDS treatment and research units, extensive community service organizations, active volunteers, hospices, visiting nurses, AIDS information hot lines, confidential testing sites, outpatient infusion centers, integration of research and clinical care, and new roles for health professionals including AIDS as an unofficial medical subspecialty. Patient care has replaced medical care, and nurture and technology must coexist when a cure cannot be assured. Physicians expecting choice in patients they care for must accept HIV; staggering health care costs, a sorely taxed public care system, fear of infection or medical inadequacy, declining nursing school enrollment, decreased interest in primary care medical specialties, a dwindling supply of community volunteers, and sparse extended care facilities hamper our efforts to provide for AIDS patients. However, the abundance of vacant hospital beds, the social and scientific challenge of AIDS care and research, employment opportunities, and a new generation of health care professionals accepting AIDS as part of the challenge of medicine all offer hope for change. In AIDS, we have the opportunity to strike an alliance between the art of healing and the advanced technology of modern medicine. In doing so, we will all face our own mortality.

Treatment of patients with acquired immunodeficiency syndrome and associated manifestations.

Treatment of AIDS is multidisciplinary and often involves input from a number of medical subspecialties. Treatment of opportunistic infections and malignancies in AIDS is largely palliative in that these treatments do not reverse the underlying immunodeficiency. Investigational approaches to the treatment of this syndrome with immunomodulators and antiviral agents are currently being investigated with the hope that these agents, either alone or in combination, will be active against this devastating disease.

Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome.

This report reviews the use of trimethoprim-sulfamethoxazole (TMP-SMZ) in individuals with Pneumocystis carinii pneumonitis (PCP) and the acquired immunodeficiency syndrome (AIDS). Before AIDS, TMP-SMZ was at least as effective as pentamidine in pediatric and adult populations and was notably less toxic. In a study prospectively comparing TMP-SMZ with pentamidine in patients with AIDS, the toxicity associated with either therapy was very high, a problem suggesting a need for the development of additional types of therapy. There was no difference in the clinical responses to the different therapeutic regimens; the majority of patients showed some improvement. The rates of both major and minor toxic reactions were similar in the two groups, although the reactions differed qualitatively. In patients with AIDS rash was frequently associated with TMP-SMZ therapy and was almost never associated with pentamidine therapy. Neutropenia was common with both drugs. Pentamidine may produce hypoglycemia, which, though infrequent, may be life threatening. Neutropenia and rash are two adverse effects of TMP-SMZ therapy being described with great frequency in patients with AIDS. Mild neutropenia is common in patients with AIDS, even when therapy is not being administered. The high rate of toxic reactions limits the usefulness of TMP-SMZ for routine prophylaxis.

Therapy of acquired immune deficiency syndrome with recombinant interleukin-2.

Recombinant human interleukin-2 (rIL-2) was administered to 87 patients with the acquired immune deficiency syndrome (AIDS) to test the hypothesis that this lymphokine would correct the underlying qualitative and quantitative deficiency in cellular immunity. Patients were divided into two groups by the presence or absence of Kaposi's sarcoma and subjects within each of these groups received intravenous rIL-2 three times weekly for eight weeks. Subjects received one of several doses which ranged from 1,000 to 2,000,000 units per square meter body surface area. Toxicity at high doses consisted of flu-like symptoms and hypotension at highest doses. Partial objective tumor regression was observed in three patients with Kaposi's sarcoma. Seventeen patients had progression of disease (new opportunistic infection or increase in Kaposi's sarcoma) during therapy. No improvement in immunologic status was observed. This study does not suggest a role for single-agent rIL-2 therapy of established AIDS but its use in less symptomatic persons or in conjunction with antiretroviral agents such as azidothymidine should be investigated.

Use of a specific and sensitive assay to determine pentamidine pharmacokinetics in patients with AIDS.

The first-dose pharmacokinetics of pentamidine were studied in patients with AIDS. Pentamidine isethionate (4 mg/kg) was administered intramuscularly or intravenously to two groups of six patients each. Serial plasma and urine concentrations were measured by high-performance liquid chromatography, which is accurate and precise (sensitivity limits, 2.29 ng/ml in plasma and 229 ng/ml in urine). The mean peak concentrations in plasma after intramuscular and intravenous administration were 209 ng/ml and 612 ng/ml, respectively. Plasma concentrations, which declined biexponentially, were detectable throughout the 24-hr dosing interval and fell to less than 25 ng/ml after 8 hr. The mean plasma clearance, elimination half-life, apparent volume of distribution, and apparent volume at steady state for intramuscularly treated patients were 305 liters/hr, 9.36 hr, 924 liters, and 2,724 liters, respectively; these parameters for intravenously treated patients were 248 liters/hr, 6.40 hr, 140 liters, and 821 liters, respectively. Renal clearance of pentamidine was 5.0% of the plasma clearance for intramuscularly treated patients and 2.5% for intravenously treated patients. We found significant differences in the pharmacokinetic parameters between intramuscularly and intravenously treated patients.

Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective randomized trial.

Forty patients with the acquired immunodeficiency syndrome (AIDS) and their first episodes of Pneumocystis carinii pneumonia were assigned at random to receive either trimethoprim-sulfamethoxazole or pentamidine isethionate. The two groups did not differ significantly in the severity of pulmonary or systemic processes at enrollment. Five patients treated initially with trimethoprim-sulfamethoxazole and one patient treated initially with pentamidine died during the 21-day treatment period (p = 0.09, Fisher's exact test). No significant differences were seen between groups in rates of improvement, pulmonary function tests, or 67Ga uptake by the lungs in the survivors at completion of therapy. Adverse reactions necessitated changing from the initial drug in 10 patients in the trimethoprim-sulfamethoxazole group and 11 in the pentamidine group. Minor reactions occurred in all patients. In patients with AIDS, trimethoprim-sulfamethoxazole and pentamidine do not have statistically significant differences in efficacy or frequency of adverse reactions.