Gail Skowron

Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections: a phase I and II study

STUDY OBJECTIVE To determine the safety and efficacy of dideoxycytidine in patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. DESIGN A partially randomized phase I and II outpatient, dose-ranging study. SETTING Four university medical centers involving government-supported referral AIDS Clinical Trial Units. PATIENTS Sixty-one patients with AIDS or advanced AIDS-related complex and 100 pg/mL or more serum p24 antigen titers. INTERVENTIONS Dideoxycytidine was administered orally at 0.06, 0.03, 0.01, or 0.005 mg/kg body weight every 4 hours for 3 to 6 months depending on tolerance and benefit. MEASUREMENTS AND MAIN RESULTS In patients receiving 0.06 and 0.03 mg/kg, diffuse erythematous rash, fever, and aphthous stomatitis occurred in the first weeks of therapy, but resolved later. Hematopoietic suppression was rare. Peripheral sensory neuropathy occurred in patients receiving 0.06 mg/kg and 0.03 mg/kg and improved after discontinuation of therapy. Serum p24 antigen fell significantly (P less than 0.01) from baseline entry values in most of these patients. The CD4 lymphocytes rose transiently at the 0.03 mg/kg dosage. At the 0.005 mg/kg dosage, skin rash, fever, and aphthous stomatitis were mild or absent. Peripheral neuropathy, which occurred in all patients receiving 0.01 mg/kg was less severe than at higher dosages. At the 0.005 mg/kg dosage, peripheral neuropathy was occasionally seen. Significant suppression of serum p24 antigen was seen in most patients with AIDS-related complex receiving 0.01 mg/kg and less frequently in patients receiving 0.005 mg/kg. CONCLUSIONS Less toxic regimens of dideoxycytidine merit clinical assessment for advanced anti-human immunodeficiency virus-1 (HIV) infection. Several studies alternating dideoxycytidine and zidovudine are in progress.

Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group Protocol 384

BACKGROUND Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized. METHODS Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113. RESULTS Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (<or=350 cells/mm(3)). These immune imbalances were most notable for those initiating ART with a baseline CD4(+) cell count <or=200 cells/mm(3), even after adjustment for baseline plasma HIV RNA levels. CONCLUSIONS After nearly 3 years of ART, T cell subsets in patients with baseline CD4(+) cell counts >350 cells/mm(3) achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART with <or=350 CD4(+) cells/mm(3) generally did not regain normal CD4(+) naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm(3) and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4(+) cell counts.

Persistent and Relapsing Babesiosis in Immunocompromised Patients

BACKGROUND Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. METHODS We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. RESULTS All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. CONCLUSIONS Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for >or=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates.

Objective: The routine use of phenotypic drug resistance testing in patient management has revealed that many HIV-1 strains possess significantly increased drug sensitivity, or ‘hypersusceptibility’ compared with wild-type viruses. This study describes hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) and was designed to determine the prevalence of and viral characteristics associated with NNRTI hypersusceptibility in patient-derived viruses. Methods: Retrospective analyses were performed on a large clinical laboratory dataset containing phenotypic drug susceptibility and genotypic sequence results from HIV-1 patient isolates. Genetically engineered viruses were used to confirm the role of certain nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations in NNRTI hypersusceptibility. Results: Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7, 10.8 and 8.0% of more than 17 000 consecutive plasma samples submitted for phenotypic susceptibility testing. In analyses limited to a subset of viruses derived from patients with known treatment histories, NNRTI hypersusceptibility was observed significantly more frequently among viruses from NRTI experienced/NNRTI-naive patients compared with viruses from NRTI/NNRTI-naive patients. Significant inverse correlations between NRTI and NNRTI susceptibility exist among the viruses from NRTI-experienced patients. Analyses of viruses classified according to their NNRTI susceptibility identified 18 positions in reverse transcriptase where substitutions were significantly associated with NNRTI hypersusceptibility. Conclusions: NNRTI hypersusceptibility is common among patient HIV-1 isolates, especially in NRTI-resistant viruses. Genotypic correlates of hypersusceptibility are complex and not easily defined by a simple analysis of NRTI-associated resistance mutations. NNRTI hypersusceptibility may provide an explanation for the superior virologic response to NNRTI-containing salvage regimens observed in NRTI-experienced patients in several clinical trials.

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

SummaryThe 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 106 IU/m2 were well tolerated and, in the presence of ZDV, did not induce increases in p24 antigenemia. Significant (p < 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 < 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.

Preventing transfusion-transmitted babesiosis: preliminary experience of the first laboratory-based blood donor screening program

BACKGROUND: Babesiosis is the most common transfusion‐transmitted infection reported to the Food and Drug Administration (FDA). We developed and implemented the first laboratory‐based blood donor screening program for Babesia microti to help reduce and prevent transfusion‐transmitted babesiosis (TTB) and report results for the initial year.

Reanalysis of Coreceptor Tropism in HIV-1–Infected Adults Using a Phenotypic Assay with Enhanced Sensitivity

The enhanced-sensitivity Trofile assay (TF-ES; Monogram Biosciences) was used to retest coreceptor tropism samples from 4 different cohorts of HIV-1-infected patients. Nine percent to 26% of patients with CCR5-tropic virus by the original Trofile assay had CXCR4-using virus by TF-ES. Lower CD4 cell counts were associated with CXCR4-using virus in all cohorts.

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

Zidovudine is a nucleoside analog that reduces progression of human immunodeficiency virus type 1 (HIV)-associated disease and prolongs survival [1-3]. The use of this drug at high doses in patients with advanced disease has been limited by hematologic toxicity [4-6]. Initial studies of another nucleoside analog, 2,3-dideoxycytidine (ddC), have shown that it is a potent inhibitor of HIV replication; therapy with ddC results in both the rapid suppression of serum p24 antigen levels and increases in CD4 cell counts [7, 8]. The principal dose-limiting toxicity of ddC is sensory peripheral neuropathy, which is related to both dose and duration of therapy [7-10]. Both zidovudine and ddC have been studied at lower doses to construct a tolerable monotherapy regimen [2, 6, 9, 11]. Alternating courses of zidovudine and ddC have been studied in an attempt to reduce dose-limiting toxicity. By limiting the continuous administration of each drug, the use of alternating therapy may allow any short-term toxicity from one drug to resolve during the administration of the other, and cumulative toxicity may be avoided. In addition to a reduction in toxicity, several other benefits of alternating therapy have been suggested. First, such combination therapy may have a synergistic or additive effect on virologic and immunologic markers; preliminary studies in vitro and in vivo suggest that alternating regimens have an enhanced antiretroviral effect [7, 12]. Concurrent zidovudine and ddC therapy has shown similar in vitro and in vivo effects and has recently been approved for use by the Food and Drug Administration [13, 14]. Second, it may be possible to maintain continuous high-dose therapy, thereby maximizing central nervous system concentrations. Third, in limiting the time of exposure to each drug, the sequential use of two agents may reduce or retard the emergence of drug-resistant isolates. We evaluated monthly and weekly alternating schedules of zidovudine and ddC to determine whether a reduction in toxicity or an enhanced antiretroviral effect, or both, could be achieved by this method of administration of the two agents. Intermittent zidovudine and ddC limbs were included to assess the relative contribution of each of the components to the overall effect. Continuous zidovudine, 1200 mg/d, served as the control treatment regimen. Methods Patients The study sample consisted of patients with AIDS-related complex or AIDS. We defined AIDS-related complex as the documented presence of one of the following: weight loss exceeding 15 pounds or 10% of body weight within 120 days before entry; a temperature greater than 38.5 C that persisted for more than 14 consecutive days or was documented on more than 15 days in a 30-day interval; diarrhea (three or more liquid stools per day) for at least 30 days without a definable cause; recurrent oral candidiasis; hairy leukoplakia; or a history of herpes zoster. We defined AIDS according to Centers for Disease Control criteria [15]. All study patients had circulating serum p24 antigen levels of 70 pg/mL or more on two occasions before enrollment. No restriction was placed on entry CD4 cell count. Patients were excluded from the study if they met any of the following criteria: a hemoglobin concentration of less than 95 g/L; transfusion dependence; an absolute granulocyte count less than 1.2 109/L; a platelet count less than 100 109/L; a calculated creatinine clearance rate of 50 mL/min per 1.73 m2 body surface area or less; transaminase levels 5 or more times the upper limit of normal; a Karnofsky performance score of less than 60; pregnancy or lactation; significant malabsorption; cardiac or liver disease; or AIDS-defining conditions requiring systemic maintenance chemotherapy. Patients with evidence of preexisting peripheral neuropathy and those who had had previous ddC treatment were also excluded. We encouraged all patients with less than 200 CD4 cells/mm3 to undergo aerosolized pentamidine prophylaxis (300 mg every month) for Pneumocystis carinii pneumonia. Study Design An unblinded, randomized trial (Protocol 047) was conducted at 12 AIDS Clinical Trials Units. Seven regimens were tested (Figure 1). At the time the study began, the standard zidovudine dose was 200 mg every 4 hours. Figure 1. The seven treatment regimens. Randomization was stratified by center and according to CD4 cell count (> 200 cells/mm3 or 200 cells/mm3). At least 16 patients were assigned to each limb. Patients who did not complete the first 8 weeks of therapy for any reason other than toxicity were replaced. All study patients gave informed consent and institutional review board approval was obtained at each institution. Study medication was to be administered for up to 49 weeks, with an additional follow-up period of 3 weeks. Study patients being treated with an intermittent regimen who had less than a 50% reduction in the serum p24 antigen level at 6 months had the option to change to an alternating regimen. Patients who completed 49 weeks of therapy and showed evidence of a beneficial response (defined as a 50% reduction in p24 antigen level or an improvement in CD4 cell count) had the option to continue therapy past 52 weeks. For the present analyses, only the first 48 weeks of data were used. Patient Evaluation Pretreatment evaluations included a medical history, physical examination, weight measurement, Karnofsky score, complete blood count, hepatic and renal function studies, T-cell subset analysis, and serum p24 antigen determination (Abbott Laboratories, North Chicago, Illinois). Follow-up evaluation was done weekly for the first 8 weeks and every 4 weeks thereafter. Serum specimens for p24 antigen determination were collected weekly for the first 8 weeks and then 3 of every 4 weeks thereafter. An evaluation for peripheral neuropathy was done on enrollment and was repeated as follows: neuropathy symptom questionnaire every 2 weeks, peripheral neurologic examination every 4 weeks, and quantitative sensory testing of vibration every 8 weeks [10]. Signs or symptoms suggestive of opportunistic infection or malignancy were evaluated according to standard AIDS Clinical Trials Group guidelines [15]. Hematologic toxicity for patients being treated with a zidovudine-containing regimen was defined and managed as follows: Transfusion was allowed for symptomatic grade 2 anemia (hemoglobin, 80 to 94 g/L) and for grade 3 (hemoglobin, 65 to 79 g/L) or grade 4 anemia (hemoglobin < 65 g/L). Study drug dosage was reduced or held in cases of grade 3 or 4 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; or in cases of grade 3 (granulocyte count, 500 to 750; leukocyte count < 1.5 109/L) or grade 4 (granulocyte count >500, leukocyte count < 1.0 109/L) granulocyte-leukocyte toxicity. Patients were removed from the study if they developed grade 3 or 4 anemia or granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred. Patients treated with intermittent ddC were removed from the study for the following reasons: a first episode of grade 3 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; grade 3 granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred; or a first episode of grade 4 anemia or granulocyte-leukocyte toxicity. Dose-limiting peripheral neuropathy was defined by the occurrence of bilateral burning or shooting pains in the lower extremities that were of moderate (grade 2) intensity and persisted for 72 hours or more; a symptom of severe (grade 3) intensity of any duration; or a symptom of moderate intensity of any duration plus either a supporting abnormality in the affected limb on standardized peripheral nerve examination or a supporting abnormality in the affected limb on quantitative sensory testing. Statistical Analysis Data from all enrolled patients were used in the analyses; however, data collected beyond the point at which patients switched from their initially assigned therapy were not included in the analysis. The Fisher exact test and chi-square tests were used to compare subgroups when the data were discrete [16] and Wilcoxon-Mann-Whitney tests were used for continuous data [17]. The Kaplan-Meier method and log-rank tests were used to analyze time-to-event data [18]. All P values were two-sided. The area under the curve (AUC) of absolute CD4 cells/mm3 was calculated, and the resulting total area was divided by time on therapy (T) to derive AUC/T [19]. The baseline CD4 count was subtracted from AUC/T to obtain the average change in CD4 cell count from baseline. A linear regression model was then calculated, with the average change in CD4 cell count as the dependent variable and both the baseline CD4 cell count and the assigned treatment limb as the independent variables. Results Patients One hundred thirty-one patients were enrolled in the study between 24 June 1988 and 17 October 1989 (Table 1). Most patients were male (96%) and white (76%) and had not received zidovudine within 90 days of study entry (96%). Seventy-seven percent had AIDS-related complex and 23% had AIDS. The median CD4 cell count at entry was 142 cells/mm3, and the median serum p24 antigen level was 257 pg/mL. Table 1. Patient Characteristics at Study Entry* The median follow-up for the entire study group was 40 weeks. Fifty-nine patients (45%) completed 48 weeks of therapy (Table 2). Twenty patients were withdrawn from the study because of toxicity related to ddC or zidovudine. Twenty-eight patients were removed because of AIDS-related opportunistic infection, malignancy, or dementia; 13 of these patients were removed from the study before completing 8 weeks of therapy. These 13 patientsalong with 4 patients who voluntarily withdrew from the study, were lost to follow-up, or were removed from the study for protocol violations in the first 8 weekswere

Safety and tolerance of dideoxycytidine as a single agent: Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex

Abstract Phase I and II clinical studies have been conducted to test the safety and potential activity of the reverse transcriptase inhibitor, dideoxycytidine (ddC), in treating human immunodeficiency virus-1-infected patients. Although ddC appears to be active in combating viral infection, as judged by its ability to decrease human immunodeficiency virus-1 p24 antigen titers and increase the number of CD4 + lymphocytes, it is also capable of causing severe peripheral neuropathy in adose-dependent manner. The studies discussed here indicate that low-dose ddC treatment regimens substantially reduce the toxic side effects of this drug, and yet retain the ability to affect p24 antigen and CD4 + lymphocyte levels. These studies also define the window of therapeutic usefulness for ddC, and suggest that both safety and activity can be maintained during long-term, low-dose use of ddC.

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.