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Biomedical subjects

Jeffrey M Jacobson

Publications and source records attributed to Jeffrey M Jacobson.

16 recordsLinked to original sources
PubMed2006

Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068.

BACKGROUND: The ability to control human immunodeficiency virus (HIV) replication in vivo in the absence of antiretroviral therapy (ART) is a measure of the efficiency of antiviral immunity. In a study of patients with chronic, ART-suppressed HIV infection, AIDS Clinical Trials Group 5068 investigated the effects of immunization with an exogenous HIV vaccine and pulse exposure to the subject's unique viral epitopes, by means of structured treatment interruptions (STIs), on the dynamics of viral rebound during a subsequent analytical treatment interruption (ATI). METHODS: Ninety-seven subjects receiving stable ART with an HIV-1 RNA load <50 copies/mL and CD4(+) T lymphocyte count >400 cells/mm(3) were randomized to undergo continued ART, STIs, ALVAC-HIV vCP1452 immunization, or STIs and ALVAC-HIV vCP1452 immunization. RESULTS: Subjects in the 2 STI arms had a significantly longer median doubling time in the period of the initial rise of viral load, a significantly lower median peak viral load, a significantly lower median end-of-ATI viral load set point, and a greater proportion of subjects with an end-of-ATI viral load set point <1,000 copies/mL, compared with the subjects in the 2 arms without STIs. With an immunization schedule of 3 sets of 3 weekly injections, ALVAC-HIV vCP1452 did not affect viral load measures. CONCLUSIONS: In this randomized, controlled study of intermittent STI as a therapeutic autoimmunization strategy, evidence of enhanced immunologic control of HIV replication was demonstrated.

AIDS Vaccines↗
PubMed2006

Low-level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton.

Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day(-1) (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P <0.05) than in age-matched controls. Bone formation rates (BFR.BS(-1)) on the endocortical surface of the metaphysis were 30% greater (P <0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately, reduce the incidence of osteoporosis or stress fractures later in life.

Animals↗
PubMed2006

Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127.

Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti-HBV activity of TDF compared to ADV in HIV/HBV-coinfected subjects. ACTG A5127 was a prospective randomized, double-blind, placebo-controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA >/= 100,000 copies/mL, and plasma HIV-1 RNA </= 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty-two subjects were randomized. At baseline, 73% of subjects had a plasma HIV-1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52 IU/L, and 98% had compensated liver disease. The mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG(48)) was -4.44 log(10) copies/mL for TDF and -3.21 log(10) copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV.

Adenine↗
PubMed2006

A pilot study evaluating time to CD4 T-cell count <350 cells/mm(3) after treatment interruption following antiretroviral therapy +/- interleukin 2: results of ACTG A5102.

BACKGROUND: Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy. METHODS: The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of <350 cells/mm as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts of > or =500 cells/mm or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n = 23) or arm B (ART alone, n = 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count of > or =500 cells/mm or more stopped ART until a CD4 count of <350 cells/mm (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms. RESULTS: IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8. CONCLUSIONS: IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.

Adult↗
PubMed2005

Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.

OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Adult↗
PubMed2005

Immune-based therapies: an adjunct to antiretroviral treatment.

Combination antiretroviral therapy potently suppresses HIV replication, but does not eradicate the infection. Drug resistance and long-term toxicities limit its use. The recovery of general immune function is often not complete. Immune-based therapies have the potential to boost HIV-specific immunity and reduce the need for antiretroviral drugs, and to promote general immune competence in situations in which antiretroviral treatment alone is inadequate. Strategies to reduce the immunopathogenic consequences of HIV infection with immunomodulating therapies are conceivable. Ultimately, eradication of the infection will require methods to target the latent memory T-cell reservoir of virus.

Anti-HIV Agents↗
PubMed2005

Sedation during voiding cystourethrography: comparison of the efficacy and safety of using oral midazolam and continuous flow nitrous oxide.

PURPOSE: We compare the efficacy and safety profile of oral midazolam and continuous flow 50% nitrous oxide (N(2)O) for alleviating anxiety and pain during voiding cystourethrography (VCU) in children. MATERIALS AND METHODS: This prospective, randomized clinical trial study was conducted in the radiology unit of a tertiary care center. Children older than 3 years scheduled for VCU were given either 0.5 mg/kg midazolam orally or continuous flow 50% N(2)O. Main outcomes were degree of anxiety and pain as assessed by the attending nurse and radiologist performing the test using a behavioral anxiety score, a distress score and an overall satisfaction score, side effects and recovery profile. RESULTS: The study included 47 children (89% girls) with a mean age of 6 years (range 3 to 15). There were 24 subjects in the midazolam group and 23 in the N(2)O group. Midazolam and N(2)O provided adequate anxiety and pain relief to perform the examination, yet children given N(2)O required less restraining and experienced a significantly shorter recovery time (29 +/- 10 vs 63 +/- 25 minutes, p <0.001). CONCLUSIONS: Continuous flow 50% nitrous oxide and oral midazolam are comparably safe and effective in reducing anxiety and distress during VCU in children older than 3 years. However, N(2)O provides a more rapid onset of sedating effect and has a shorter recovery time.

Administration, Inhalation↗
PubMed2004

HIV-related pneumonia care in older patients hospitalized in the early HAART era.

Age-related variations in care have been identified for HIV-associated Pneumocystis carinii pneumonia (PCP) in both the 1980s and 1990s. We evaluated if age-related variations affected all aspects of HIV-specific and non-HIV-specific care for HIV-infected individuals with PCP or community-acquired pneumonia (CAP), or whether age-related variations were primarily limited to HIV-specific aspects of care. Subjects were HIV-infected persons with PCP (n = 1855) or CAP (n = 1415) hospitalized in 8 cities from 1995 to 1997. Nine percent of our study patients had received protease inhibitors and 39% had received any type of antiretroviral therapy prior to hospitalization. Data were abstracted from medical records and included severity of illness, HIV-specific aspects of care (initiation of PCP medications), general measures of care [initiation of CAP medications, intubation, and intensive care units (ICU)], and inpatient mortality. Compared to younger patients, pneumonia patients 50 years of age or older were significantly more likely to: be severely ill (PCP, 20.4% vs. 10.4%; CAP, 27.5% vs. 14.9%; each p = 0.001), receive ICU care (PCP, 22.0% vs. 12.8%, p = 0.002; CAP: 15.1% vs. 9.4%; p = 0.02), and be intubated (PCP, 14.6% vs. 8.4%, p = 0.01; CAP, 9.9% vs. 5.6%, p = 0.03). Compared to younger patients, older patients (>/=50 years) had similar rates of timely medications for CAP (48.5% vs. 50.8%) but had lower rates of receiving anti-PCP medications (85.8% vs. 92.9%, p = 0.002). Differences by age in timely initiation of PCP medications, ICU use, and intubation were limited to the nonseverely ill patients. Older hospitalized patients were more likely to die (PCP, 18.3% vs. 10.4%; CAP, 13.4% vs. 8.5%; each p < 0.05). After adjustment for disease severity and timeliness of antibiotic use, mortality rates were similar for both age groups. Physicians should develop strategies that increase awareness of the possibility of HIV infection in older individuals.

AIDS-Related Opportunistic Infections↗
PubMed2004

Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542.

Viral entry inhibitors represent an emerging mode of therapy for human immunodeficiency virus type 1 (HIV-1) infection. PRO 542 (CD4-immunoglobulin G2) is a tetravalent CD4-immunoglobulin fusion protein that broadly neutralizes primary HIV-1 isolates. PRO 542 binds to the viral surface glycoprotein gp120 and blocks attachment and entry of virus into CD4(+) cells. Previously, PRO 542 demonstrated antiviral activity without significant toxicity when tested at single doses ranging to 10 mg/kg. In this study, 12 HIV-infected individuals were treated with 25-mg/kg single-dose PRO 542 and then monitored for safety, antiviral effects, and PRO 542 pharmacokinetics for 6 weeks. The study examined two treatment cohorts that differed in the extent of HIV-1 disease progression. PRO 542 at 25 mg/kg was well tolerated and demonstrated a serum half-life of 3 days. Statistically significant acute reductions in HIV-1 RNA levels were observed across all study patients, and greater antiviral effects were observed in the cohort of patients with more advanced HIV-1 disease. In advanced disease (HIV-1 RNA > 100,000 copies/ml; CD4 lymphocytes < 200 cells/mm(3)), PRO 542 mediated an 80% response rate and statistically significant approximately 0.5 log(10) mean reductions in viral load for 4 to 6 weeks posttreatment. Similar findings were obtained in an analysis of all (n = 11) advanced disease patients treated to date with single doses of PRO 542 ranging from 1 to 25 mg/kg. In addition, a significant correlation was observed between antiviral effects observed in vivo and viral susceptibility to PRO 542 in vitro. The findings support continued development of PRO 542 for salvage therapy of advanced HIV-1 disease.

Adult↗
PubMed2003

Granulocyte-macrophage colony-stimulating factor induces modest increases in plasma human immunodeficiency virus (HIV) type 1 RNA levels and CD4+ lymphocyte counts in patients with uncontrolled HIV infection.

BACKGROUND: Studies have reported that plasma human immunodeficiency virus type 1 (HIV-1) RNA levels and CD4+ lymphocyte counts in HIV-infected patients improved after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: In AIDS Clinical Trials Group Protocol 5041, 116 patients were enrolled in a double-blind, randomized, placebo-controlled clinical trial of 16 weeks of 250 microg of GM-CSF administered subcutaneously 3 times/week, followed by open-label treatment for an additional 32 weeks. Patients had stable baseline plasma HIV-1 RNA levels of > or =1500 copies/mL and received constant antiretroviral regimens through at least the first 16 weeks of the study. RESULTS: After 16 weeks, the GM-CSF group tended to have greater, though clinically insignificant, increases in plasma HIV-1 RNA levels, compared with the placebo group (median change, +0.048 vs. -0.103 log copies/mL; P=.036, in a post hoc analysis). There were trends toward progressive modest increases in CD4+ lymphocyte counts with GM-CSF treatment at 16 weeks (median change, +14 vs. -6 cells/mm3; P=.06) and beyond. CONCLUSIONS: GM-CSF does not have an antiviral effect in patients with ongoing HIV replication but may increase CD4+ lymphocyte counts.

Adult↗
PubMed2003

A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3).

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.

Adult↗
PubMed2002

Type II single umbilical artery (persistent vitelline artery) in an otherwise normal fetus.

A single umbilical artery resulting from absence of the umbilical arteries and persistence of the vitelline artery that arises directly from the abdominal aorta has been described only in malformed fetuses with sirenomelia or caudal regression. Such an aberrant artery was suggested to be the etiology of sirenomelia caused by a 'steal' mechanism of blood flow from the caudal end of the embryo. We present a case in which prenatal ultrasound showed a similar aberrant single artery arising from the abdominal aorta in an otherwise normal fetus with a normal course of pregnancy. This vessel, a continuation of the superior mesenteric artery (SMA), corresponds to a persistent vitelline artery assuming the function of the umbilical arteries. The etiology of such a finding and its possible consequences are discussed.

Adult↗
PubMedDate not supplied

The prevalence of distress in persons with human immunodeficiency virus infection.

The purpose of this study was to assess the prevalence of distress, anxiety, and depression in persons with human immunodeficiency virus (HIV) infection and determine the feasibility of screening in an urban HIV primary care setting. A convenience sample of 101 patients in the waiting room of an acquired immunodeficiency syndrome clinic completed two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Distress Thermometer. The patient's demographic, medical, and psychiatric histories were obtained through chart review. The results of the Distress Thermometer revealed that 72.3% had a score of 5 or greater, demonstrating high distress. The results of the HADS revealed that 70.3% had high anxiety, with a score of 7 or greater. On the HADS depression questions, 45.5% had a score of 7 or greater, indicating depression. Analysis of the total HADS scores, including anxiety and depression, revealed that 53.5% had a score of greater than 15 and were experiencing significant distress. Patients with high viral loads were more likely to be distressed (P < 0.0005). Patients with high viral loads were also more likely to have higher anxiety or depression scores on the HADS. Patients who had CD4 counts higher than 500/mm(3) were less likely to be depressed. This study demonstrates a high prevalence of distress, anxiety, and depression among persons with HIV. The HADS and the Distress Thermometer showed a good correlation with each other (P < 0.0005), and these questionnaires can provide a simple and efficient method for rapid screening in an HIV clinic setting.

Adult↗