T-Cell Responses in Adults During Natural Respiratory Syncytial Virus Infection.

Background: The pathogenesis of respiratory syncytial virus (RSV) in older adults may be due to age-related T-cell immunosenescence. Thus, we evaluated CD4 and CD8 T-cell responses during RSV infection in adults across the age spectrum. Methods: Peripheral blood mononuclear cells collected during RSV infection in adults, age 26-96 years, were stimulated with live RSV and peptide pools representing F, M, NP, and G proteins and analyzed by flow cytometry. Results: There were no significant age-related differences in frequency of CD4+ T cells synthesizing interferon (IFN)γ, interleukin (IL)2, IL4, IL10, or tumor necrosis factor (TNF)α or in CD8+IFNγ+ T cells. IL4+CD4+ T-cell numbers were low, as were IL13 and IL17 responses. However, in univariate analysis, CD4 T-cell IFNγ, IL2, IL4, IL10, and TNFα responses and CD8+IFNγ+ T cells were significantly increased with more severe illness requiring hospitalization. In multivariate analysis, viral load was also associated with increased T-cell responses. Conclusions: We found no evidence of diminished RSV-specific CD4 or CD8 T-cell responses in adults infected with RSV. However, adults with severe disease seemed to have more robust CD4 and CD8 T-cell responses during infection, suggesting that disease severity may have a greater association with T-cell responses than age.

Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS.

OBJECTIVE: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. DESIGN: A phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine. SETTING: Eight clinical sites in the United States. PATIENTS: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. METHODS: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. MAIN OUTCOME MEASURES: Patient response was evaluated clinically and radiologically. RESULTS: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. CONCLUSION: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.

Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260).

The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team.

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.

Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258.

BACKGROUND: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. OBJECTIVE: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. DESIGN: Phase I study. SETTING: Four clinical research units. PATIENTS: 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. INTERVENTION: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. MEASUREMENTS: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. RESULTS: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. CONCLUSIONS: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied.

Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients.

The safety, tolerability, and antiviral activity of atevirdine (ATV), a nonnucleoside reverse transcriptase inhibitor, were studied in a phase I/II clinical trial (ACTG 187) of patients with CD4 counts < or =500/mm3. In all, 34 HIV-1-infected patients were randomized to receive ATV for 12 weeks in doses chosen to achieve one of three serum trough levels: 5 to 13 microM, 14 to 22 microM, or 23 to 31 microM. Rash was the most common adverse event, with a grade 3 or 4 rash occurring in 4 patients. No significant change from baseline in HIV-1 plasma RNA mean copy number was detected at week 4 (+0.09 log10 copies/ml; p = .30). However, some evidence indicated moderate antiviral activity at week 4, based on median changes in CD4 count (+23/mm3; p = .05), and viral peripheral blood mononuclear cell (PBMC) titer (-0.68 log10) copies/ml; p = .03). In addition, 2 of 4 patients with detectable baseline serum p24 antigen showed declines of >50%. HIV-1 resistance to ATV was detected in 41% of patients and was most commonly associated with RT mutations K103N and Y181C. In contrast, the Y181C mutation was not detected in ATV-resistant isolates obtained from patients enrolled in ACTG 199, a study of ATV given in combination with zidovudine. Under the conditions of this study, ATV failed to demonstrate significant antiretroviral activity. However, transient in vivo activity might have been obscured by rapid development of resistance coupled with inadequate sampling at early time points following initiation of ATV therapy.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE: Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS: Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS: The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION: TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. AIDS Clinical Trials Group Study 197.

We conducted a three-arm, randomized, phase II study to evaluate the combination of zidovudine (600 mg/day) and zalcitabine (2.25 mg/day) alone or with one of two interferon-alpha2a doses (1 mIU or 6 mIU daily). Primary study endpoints included toxicity and changes from baseline for plasma HIV-1 RNA, CD4 cells, and quantitative microculture at weeks 8 and 24. Sixty-three patients with HIV infection and <400 CD4 cells/mm3 were enrolled; four patients discontinued therapy within 2 weeks. Adverse event rates were 37%, 32%, and 60%, respectively, for the nucleoside, 1-mIU interferon, and 6-mIU interferon combination groups. Increasing doses of interferon resulted in significantly greater hematologic toxicity (p = 0.03) and peripheral neuropathy (p = 0.02). Plasma HIV-1 RNA reductions were noted across all treatment groups at week 8 (p < 0.001) but only for the nucleoside and 1-mIU interferon combination groups at week 24 (p < 0.001). Mean reductions in HIV-1 RNA at week 8 were 0.94, 1.29, and 1.40 log10, respectively, for the nucleoside, 1-mIU interferon, and 6-mIU interferon combination groups (p = 0.05); no differences were noted at week 24. No differences in CD4 cell counts were seen. The addition of interferon-alpha2a to zidovudine and zalcitabine resulted in transient enhanced decreases in viral load and increased toxicity.

Phase I/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151.

SC-52151, an HIV-1 protease inhibitor, was developed as an ethanol-based elixir and subsequently as a self-emulsifying drug delivery system (SEDDS) to improve bioavailability. To evaluate formulation and treatment regimen effects, we conducted a four-arm, phase I/II study using the highest previously tested daily dose, 2250 mg. Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily or 1125 mg twice daily for 14 days. One patient developed hypertriglyceridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-time curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HIV. A mean decline of 0.03 log10 RNA copies (SEDDS) and an increase of 0.15 log10 (elixir) were observed. Although SC-52151 was well tolerated and the SEDDS formulation resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced.

A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team.

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.

Taste responses and food preferences in obese women: effects of weight cycling.

Taste preferences for sensory stimuli composed of sugar and fat are predictive of some food preferences and may help distinguish between potential subtypes of human obesity. A sample of 37 obese females was divided into high-flux and low-flux groups according to the magnitude of fluctuations in body weight. Variability in body weight is thought to be indicative of the weight cycling syndrome. The subjects tasted and rated five sucrose solutions in water and nine ice creams of varying sugar and fat content. Perceptions and preferences for sweet solutions were the same for both groups. In contrast, the high-flux group showed higher preferences for ice cream stimuli than did the low-flux group. High-flux females also rated sweet desserts higher on a food preference questionnaire than did low-flux females. Prior consumption of milkshake pre-loads did not affect preference ratings for sweet solutions. However, hedonic preferences for ice creams after pre-load consumption were reduced in the high-flux group. The weight cycling syndrome may be associated with elevated hedonic preferences for sweet and high fat foods.

Food preferences in human obesity: carbohydrates versus fats.

A large clinical sample of obese men and women were asked for a self-generated list of ten favorite foods. The lists were characterized by frequent instances of foods that are major nutrient sources of fat in the American diet. While obese men listed mainly protein/fat sources (meat dishes) among their favorite foods, obese women tended to list predominantly carbohydrate/fat sources (doughnuts, cookies, cake) and foods that were sweet. There was no evidence that selective preferences for a single macronutrient, carbohydrate, were a standard feature of human obesity. Rather, preferences for major nutrient sources of fat as opposed to carbohydrate may be a primary characteristic of human obesity syndromes.