Baseline CD4(+) cell count, not viral load, correlates with virologic suppression induced by potent antiretroviral therapy.

OBJECTIVE: To investigate the relationship between viral load suppression and baseline viral load as well as that between viral load suppression and baseline CD4(+) cell count. DESIGN: Meta-analysis of published and presented studies. METHODS: Trials of two nucleoside analogs plus nevirapine, indinavir, nelfinavir, or efavirenz as therapy for antiretroviral treatment-naive patients with HIV infection or AIDS who were followed-up for at least 6 months were included in the meta-analysis. The proportion of patients with viral loads of <200-500 copies/ml at 6 and 12 months (total number of patients, 1619 and 761, respectively) was regressed to the mean or median baseline viral load and CD4(+) cell count. RESULTS: Thirty-six treatment arms from 30 studies were identified. Multivariate regression demonstrated a significant correlation between baseline CD4(+) cell count and virologic suppression at 6 and 12 months ( t = 2.85, p =.008; and t = 3.08, p =.010, respectively) but not between baseline viral load and virologic suppression ( t = 0.92, p =.365; and t = 1.31, p =.215, respectively). The same pattern was seen in a subanalysis of trials of nevirapine-containing therapy (CD4(+) cell count: t = 2.89, p =.014 at 6 months; viral load suppression: t = 0.84, p =.415). CONCLUSIONS: Baseline CD4(+) cell count was a better predictor of virologic suppression induced by triple combination therapy than was baseline viral load.

A randomized study of the safety and antiretroviral activity of hydroxyurea combined with didanosine in persons infected with human immunodeficiency virus type 1. American Foundation for AIDS Research Community-Based Clinical Trials Network.

This randomized open-label trial of human immunodeficiency virus type 1-infected persons compared safety and efficacy for 38 patients receiving hydroxyurea/didanosine combination therapy with findings in 42 persons given didanosine monotherapy for 12 weeks, followed by 12 weeks of hydroxyurea/didanosine combination therapy for all patients. Week 12 on-treatment group comparisons showed a mean decrease in virus load between hydroxyurea/didanosine versus didanosine groups of -0.93 versus -0.74 log10 copies/mL (P=.20); a higher percentage of the hydroxyurea/didanosine group below the assay's detection limit (500 copies/mL), 29% versus 7% (P=.017); and median change in CD4 cells for the hydroxyurea/didanosine versus didanosine group of 0 versus 43 cells/mm3 (P=.045), although median change in CD4 percentage was similar (0.9% vs. 1.2%, P=.64). Week 24 virus load reductions and CD4 cell changes were similar in both groups. Intent-to-treat and on-treatment analyses showed similar results. The hydroxyurea/didanosine combination was well tolerated.

The safety and efficacy of granulocyte-macrophage colony-stimulating factor (Sargramostim) added to indinavir- or ritonavir-based antiretroviral therapy: a randomized double-blind, placebo-controlled trial.

Sargramostim is a yeast-derived, recombinant human granulocyte-macrophage colony-stimulating factor with therapeutic potential in human immunodeficiency virus (HIV) infection. Its safety and activity when used in combination with protease inhibitors were evaluated in a randomized, double-blind trial in which 20 HIV-infected subjects on stable antiretroviral regimens, including indinavir or ritonavir, received sargramostim or placebo 3 times a week for 8 weeks. Analysis of HIV virus load excluded any 0. 5 log10 increase due to sargramostim (95% confidence interval, -0.68 to 0.44). Sargramostim was well tolerated, and inflammatory cytokines and surrogate markers of disease progression, such as serum levels of interleukin-10 and soluble tumor necrosis factor receptors types Iota and IotaIota, remained stable in subjects receiving sargramostim. Sargramostim treatment was associated with a trend toward decreased HIV RNA (>0.5 log10) and increased CD4+ cell count (>30%). These results became statistically significant only when subjects with baseline virus loads within the limits of detection or baseline CD4 cell count >50 were analyzed. No difference in indinavir pharmacokinetics was observed before or after sargramostim therapy.

A phase I/II evaluation of oral L-2-oxothiazolidine-4-carboxylic acid in asymptomatic patients infected with human immunodeficiency virus.

A randomized double-blind, placebo-controlled study was conducted in 37 asymptomatic HIV-infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single-dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 +/- 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.

dNN study: stavudine, nelfinavir and nevirapine. Preliminary safety, activity and pharmacokinetic interactions.

The dNN study evaluated the safety, efficacy and pharmacokinetic interactions of the combination of stavudine (2',3'-didehydro-2',3'-dideoxythymidine; D4T), nelfinavir and nevirapine in 25 HIV-infected subjects who received treatment for up to 29 weeks. This brief report presents the study design and preliminary data.

gp120-directed antibody-dependent cellular cytotoxicity as a major determinant of the rate of decline in CD4 percentage in HIV-1 disease.

OBJECTIVE: To determine the relationship between the rate of CD4 percentage decline and two factors postulated to be associated with CD4 cell destruction: circulating HIV-1 viral load and gp120-directed antibody-dependent cellular cytotoxicity (ADCC). DESIGN: Four women and 16 men had serial determinations of CD4 percentage gp120-directed ADCC activity [using the cell-mediated cytotoxicity (CMC) assay] natural killer (NK) cell number, spontaneous NK lytic function, and plasma HIV-1 RNA. METHODS: The rate of decline in CD4 percentage was modeled as a function of gp120-directed ADCC activity and circulating HIV-1 RNA using Pearson correlation and multiple regression analyses. RESULTS: All individuals had at least four CMC assays performed and two HIV-1 RNA polymerase chain reaction measurements over a median follow-up of 27 months. Although the rate of CD4 percentage decline was associated with either CMC activity (r = -0.53, P = 0.02) or circulating HIV-1 RNA (r = -0.42, P = 0.07), it was strongly correlated with an interaction between CMC and HIV-1 RNA (r = -0.76, P < 0.0001). Mean CMC activity was associated with both mean percentage of circulating NK cells and mean spontaneous NK cell lysis. CONCLUSIONS: The ability of cells from HIV-infected individuals to mediate gp120-directed ADCC, together with a sufficient circulating viral load, define conditions under which rapid CD4 cell destruction may occur. This relationship between viral load and an HIV-1-specific immune response lends important insights into the central causes of immunodeficiency in AIDS and suggests additional avenues for therapeutic intervention.

The use of protease inhibitors. A sampling of opinions. Interview by Deborah J Cotton.

AIDS: In a roundtable discussion with AIDS Clinical Care, four leading HIV clinical investigators--Drs. Martin Hirsch, Stefano Vella, Lawrence Corey, and Gail Skowron--discuss their views on the state-of-the-art antiviral therapy for HIV infection: protease inhibitors. Martin Hirsch, the director of clinical AIDS research at Massachusetts General Hospital, recommends a combination of a protease inhibitor and one or two reverse transcriptase inhibitors for patients in the advanced stages of AIDS. Lawrence Corey, head of the Program in Infectious Diseases at the Fred Hutchison Cancer Center, states that protease inhibitors should not be taken alone due to the risk of developing resistance, but that they should be used with a nucleoside analog. Meanwhile, Gail Skowron, an infectious disease consultant for Roger Williams Hospital, recommends using a protease inhibitor alone if a patient is not able to tolerate other antiretrovirals, noting that more information is needed on combining protease inhibitors. A clinical trial is needed to determine if protease inhibitors should be used early or late in infection. Hirsch suggests using nucleoside combinations first and then resorting to protease inhibitors if needed. Skowron recommends treating high viral loads aggressively with combination therapy, including a protease inhibitor.^ieng

Biologic effects and safety of stavudine: overview of phase I and II clinical trials.

Data on the biologic effects and safety of stavudine in patients with AIDS and AIDS-related complex represent results of two phase I trials (n = 84), another phase I study of patients with hematologic intolerance to zidovudine (n = 23), and a phase II trial (n = 152). The daily doses of stavudine ranged from 0.1 to 12.0 mg/kg. Increases in CD4 cell count, declines in serum p24 antigen, and weight gain were all related to the dose of stavudine. Doses of < or = 2 mg/kg/day (n = 216) were well-tolerated, with a median duration of therapy of > or = 48 weeks in the phase I studies and > or = 79 weeks in the phase II study. The predominant dose-limiting toxicity was peripheral neuropathy, which was related to both the dose and duration of treatment with stavudine. Elevations of liver enzymes were seen in some patients but appeared to be related to underlying disease rather than treatment. There was no evidence of dose-related hematologic toxicity.

Zidovudine and dideoxycytidine differ in their effects on human immunodeficiency virus-induced pathologic activation of the immune system. AIDS Clinical Trial Research Group 047.

When zidovudine and dideoxycytidine (ddC) were given on schedules of 1 week on drug and 1 week off, results differed substantially in effects on HIV (human immunodeficiency virus type 1)-induced immune activation. Zidovudine (200 mg every 4 h) caused marked lowering toward normal of serum neopterin and beta 2-microglobulin within 1 week. This effect was lost within 1 week off zidovudine. Intermittent ddC (0.03 mg/kg every 4 h) had a smaller 1-week effect but had a delayed cumulative suppressive effect on HIV-associated immune activation that was not seen with intermittent zidovudine therapy. Zidovudine and ddC given in alternating weeks had synergistic effects in the first 10 weeks (e.g., early and rapid reduction followed by cumulatively greater effects on immune cell activation). The identical sawtooth effect of intermittent zidovudine was also evident in serum HIV p24 antigen levels. This is consistent with the hypothesis that the increased serum levels of the immune activation markers seen in HIV infection reflect stimulatory effects of HIV viral components on immune system cells.

A phase I/II trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (procysteine) in asymptomatic HIV-infected subjects.

Twenty-four asymptomatic, HIV-1-seropositive subjects with CD4 cell counts of > or = 400/microliters participated in a Phase I/II, dose escalation trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (OTC: Procysteine). Four groups of six subjects each were consecutively assigned to receive OTC at an initial dose of 3, 10, 30, or 100 mg/kg, followed by the same dose given twice weekly for 6 weeks. Increases in whole-blood glutathione were observed in the highest dosage group after 6 weeks of therapy. No effects on changes in CD4 cell counts, viral load, or proviral DNA frequency were observed among the four dosage groups, although a decline in beta 2-microglobulin levels was apparent in the highest dosage group. One subject withdrew due to headaches; other probable adverse events including rash, flushing, pruritus, lightheadedness, and diminished concentration were self-limited.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients.

We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.

Causes of death in persons with human immunodeficiency virus infection.

PURPOSE: Pneumocystis carinii pneumonia (PCP) was reported to be the predominant cause of human immunodeficiency virus (HIV)-related deaths prior to 1988, the year that effective prophylaxis against PCP entered routine use. Our study was performed to study the causes of HIV-related death since January 1988 in a region where patient tracking is virtually complete. PATIENTS AND METHODS: We surveyed physicians associated with the Brown University Acquired Immunodeficiency Syndrome (AIDS) Program who cared for greater than 95% of known HIV-positive patients in Rhode Island. These physicians identified all those HIV-infected persons who had died under their care between January 1988 and July 1990, and determined these patients' causes of death by chart review. For comparison, death certificates of identified persons were also reviewed at the Rhode Island Department of Vital Statistics. RESULTS: Among 126 deaths since January 1988, bacterial infections were the most common cause of death (30%), whereas PCP was responsible for only 16% of deaths. Persons not receiving any form of PCP prophylaxis were more likely to die from PCP than were those who received prophylaxis (26% versus 11% [p = 0.04]). Cause of death as recorded on actual death certificates was imprecise, although bacterial infections were again the most common cause indicated. Only one death occurred in a patient with a CD4 count greater than 200/mL, and this was not HIV-related. CONCLUSION: PCP has not been the leading cause of death in our region since January 1988. Bacterial infections contribute substantially to mortality, and this may influence future prophylactic regimens. HIV-related deaths in patients with CD4 counts greater than 200/mL are unusual.

Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: monotherapy.

At present, the nucleoside analogues are the cornerstone of therapy for HIV infection. Of the three that have been approved for clinical use, AZT is the only one that has clearly proved to prolong survival. ddI is indicated for patients who develop toxicity or resistance to AZT. Current data do not support ddC monotherapy as first-line treatment.

Safety and effects of interleukin-2 plus zidovudine in asymptomatic individuals infected with human immunodeficiency virus.

The safety of continuous i.v. interleukin-2 (IL-2) in conjunction with zidovudine (ZDV) was assessed in asymptomatic patients infected with human immunodeficiency virus. Clinical, immunologic, and viral parameters were monitored in a phase I/II trial with dose escalation and crossover arms. Daily doses of IL-2 from 1.5 to 12 x 10(6) IU/m2 were well tolerated and, in the presence of ZDV, did not induce increases in p24 antigenemia. Significant (p less than 0.05) but transient increases in CD4 cells were observed midway through infusion of IL-2 at all doses, and increases in natural and lymphokine-activated killer activity were seen at higher doses. Circulating hypodense eosinophils and soluble IL-2 receptors increased more than 10-fold. Of nine patients available for long-term follow up 13-25 months from baseline and 4-21 months after stopping IL-2, six still had improved CD4 counts (versus baseline), and the mean increase (135/mm3) for all nine patients was significant (p less than 0.05). Eight of these nine patients were negative for serum p24 at the start of therapy, and none had become p24 antigenemic at long-term follow-up.