Judith Feinberg

A Randomized Trial Comparing Fluconazole with Clotrimazole Troches for the Prevention of Fungal Infections in Patients with Advanced Human Immunodeficiency Virus Infection

Background Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. Methods We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. Results After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the cl...

A Randomized Trial of Three Antipneumocystis Agents in Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND We evaluated the effectiveness of three treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). METHODS In an open-label trial, 843 patients with HIV infection and fewer than 200 CD4+ cells per cubic millimeter received zidovudine plus one of three randomly assigned prophylactic agents, beginning with trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine and followed by a defined sequence of other drugs to be used in cases of intolerance. RESULTS The estimated 36-month cumulative risks of P. carinii pneumonia were 18 percent, 17 percent, and 21 percent in the trimethoprim-sulfamethoxazole, dapsone, and aerosolized-pentamidine groups, respectively (P = 0.22). The difference in risk among treatment strategies was negligible in patients entering the study with 100 or more CD4+ lymphocytes per cubic millimeter. In those entering with fewer than 100 CD4+ cells per cubic millimeter, the risk was 33 percent with aerosolized pentamidine, as compared with 19 percent with trimethoprim-sulfamethoxazole and 22 percent with dapsone (P = 0.04). The lowest failure rates occurred in patients receiving trimethoprim-sulfamethoxazole, and failures were more common with 50 mg of dapsone than with 100 mg. Toxoplasmosis developed in less than 3 percent of patients. Of the patients assigned to the two systemic therapies, only 23 percent were receiving their assigned drug and dose when they completed the study. The median survival was approximately 39 months in all three groups, and the mortality attributable to P. carinii pneumonia was only 1 percent. CONCLUSIONS In patients with advanced HIV infection, the three treatment strategies we examined have similar effectiveness in preventing P. carinii pneumonia. Strategies that start with trimethoprim-sulfamethoxazole or with high-dose dapsone, rather than aerosolized pentamidine, are superior in patients with fewer than 100 CD4+ lymphocytes per cubic millimeter.

Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

BACKGROUND Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

The effect of mode of administration on Medical Outcomes Study health ratings and EuroQol scores in AIDS

Brief measures of health-related quality of life are being used with increased frequency in AIDS clinical trials. Self-administration of questionnaires can reduce costs in this setting because they require little time. However, the equivalence between self- and interview-administered responses in clinical trials is not known. We evaluated patient and proxy responses to the Medical Outcomes Study HIV Health Survey (MOS-HIV) and the EuroQol. We randomized 68 patients with advanced HIV disease on (1) mode of administration (self vs. interview); (2) type of interview (face-to-face vs. telephone); (3) questionnaire order (MOS-first vs. EuroQol-first); and (4) 2- vs. 3-item response categories for physical limitations. There were few differences in scores between self and interview administration and type of interview. Proxy respondents viewed patients as more impaired than did patients themselves on subjective aspects of health including mental health (63.8 vs. 75.7, p < 0.001), health distress (67.3 vs. 77.1, p=0.007), pain (64.4 vs. 70.0, p=0.04), and vitality (48.4 vs. 55.5, p=0.04). Results concerning questionnaire order and number of response categories were not conclusive. Our results suggest that for patients with advanced HIV disease, data from the MOS-HIV and the EuroQol collected using different modes may be pooled, but that proxy responses should be calibrated.

FEVER IN PATIENTS WITH HIV INFECTION

Fever is a common sign during the course of HIV infection, usually represents a superimposed opportunistic infection, and is almost always a treatable condition. Proper management generally requires detection of the underlying cause, and the diagnostic evaluation is largely driven by the clinical symptoms, associated conditions such as injection drug use, and stage of disease based largely on the absolute CD4 cell count. This article provides guidelines for the management of fever in the patient with HIV infection.

CURRENT STATUS OF HIV THERAPY. II, OPPORTUNISTIC DISEASES

Infections and malignancies account for most deaths in patients with AIDS and will continue to do so as long as HIV-induced immunosuppression is progressive and irreversible. Co-trimoxazole has emerged as the preferred agent for prevention of Pneumocystis carinii pneumonia. As appropriate broad-spectrum agents are developed, multiple opportunistic pathogen prophylaxis could become effective.

Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173.

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia (>20%) was seen in 3 of 6 study subjects who received 150 mg/day for > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.