scholarly journals Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

2006 ◽  
Vol 51 (3) ◽  
pp. 1038-1042 ◽  
Author(s):  
Annemarie E. Brouwer ◽  
Hendrikus J. M. van Kan ◽  
Elizabeth Johnson ◽  
Adul Rajanuwong ◽  
Prapit Teparrukkul ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
Controlled Trial ◽  
Oral Formulation ◽  
Bone Marrow Toxicity ◽  
Time Curve ◽  
Immunodeficiency Virus ◽  
Early Fungicidal Activity

ABSTRACT In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.

scholarly journals In vitro potency of inhibition by antiviral drugs of hematopoietic progenitor colony formation correlates with exposure at hemotoxic levels in human immunodeficiency virus-positive humans.

1996 ◽  
Vol 40 (2) ◽  
pp. 514-519 ◽  
Author(s):  
R E Dornsife ◽  
D R Averett
Keyword(s):  
Human Immunodeficiency Virus ◽  
Colony Formation ◽  
Rank Order ◽  
Bone Marrow Toxicity ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Nucleoside Drugs ◽  
Antiviral Nucleoside

Inhibition of in vitro colony formation of human hematopoietic progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid) by the antiviral nucleoside drugs alovudine, zalcitabine, zidovudine, ganciclovir, stavudine, didanosine, lamivudine, and acyclovir was measured. Significant correlations between in vitro 50% inhibitory concentrations and the daily human exposures (area under the concentration-time curve from 0 to 24 h; in micromolar.hour) of these chronically administered drugs in human immunodeficiency virus-positive patients that induced neutropenia or anemia were demonstrated by both linear regression and Spearman rank-order analyses. These quantitative correlations allow estimation of the exposure at which bone marrow toxicity may occur with candidate compounds.

scholarly journals In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus.

1989 ◽  
Vol 33 (4) ◽  
pp. 576-579 ◽  
Author(s):  
T Inoue ◽  
K Tsushita ◽  
T Itoh ◽  
M Ogura ◽  
T Hotta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Nucleoside Analogs ◽  
Bone Marrow Toxicity ◽  
Immunodeficiency Virus

scholarly journals Six-Week Randomized Controlled Trial To Compare the Tolerabilities, Pharmacokinetics, and Antiviral Activities of GW433908 and Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients

2004 ◽  
Vol 48 (1) ◽  
pp. 116-123 ◽  
Author(s):  
Robin Wood ◽  
Keikawus Arasteh ◽  
Hans-Jürgen Stellbrink ◽  
Eugenio Teofilo ◽  
François Raffi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Controlled Trial ◽  
Gastrointestinal Symptoms ◽  
Hiv Protease ◽  
Maximum Plasma ◽  
Hiv Protease Inhibitors ◽  
Time Curve ◽  
Dosing Interval ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (τ), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUCτ,ss versus the AUC from 0 h to ∞ was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA (∼2 log10 copies/ml) and increased CD4+ cell counts (∼100 cells/mm3) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.

scholarly journals A Randomized Controlled Trial of Isoniazid to Prevent Mycobacterium tuberculosis Infection in Kenyan Human Immunodeficiency Virus–Exposed Uninfected Infants

2020 ◽  
Author(s):  
Sylvia M LaCourse ◽  
Barbra A Richardson ◽  
John Kinuthia ◽  
A J Warr ◽  
Elizabeth Maleche-Obimbo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mycobacterium Tuberculosis ◽  
High Risk ◽  
Adverse Events ◽  
Controlled Trial ◽  
Preventive Therapy ◽  
Infection Prevalence ◽  
Mycobacterium Tuberculosis Infection ◽  
Immunodeficiency Virus ◽  
Exposed Uninfected

Abstract Background Human immunodeficiency virus (HIV)–exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary Mycobacterium tuberculosis (Mtb) infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection. Methods We conducted a randomized nonblinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months of daily INH (10 mg/kg) vs no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-γ release assay (QuantiFERON-TB Gold Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit). Results Between 15 August 2016 and 6 June 2018, 416 infants were screened, with 300 (72%) randomized to INH or no INH (150 per arm); 2 were excluded due to HIV infection. Among 298 randomized HEU infants, 12-month retention was 96.3% (287/298), and 88.9% (265/298) had primary outcome data. Mtb infection prevalence at 12-month follow-up was 10.6% (28/265); 7.6% (10/132) in the INH arm and 13.5% (18/133) in the no INH arm (7.0 vs 13.4 per 100 person-years; hazard ratio, 0.53 [95% confidence interval {CI}, .24–1.14]; P = .11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH; relative risk, 0.48 [95% CI, .22–1.05]; P = .07). Frequency of severe adverse events was similar between arms (INH, 14.0% [21/150] vs no INH, 10.7% [16/150]; P = .38), with no INH-related adverse events. Conclusions Further studies evaluating TB preventive therapy to prevent or delay primary Mtb infection in HEU and other high-risk infants are warranted. Clinical Trials Registration NCT02613169.

scholarly journals Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans

2020 ◽  
Vol 7 (11) ◽  
Author(s):  
Shichina Kannambath ◽  
Joseph N Jarvis ◽  
Rachel M Wake ◽  
Nicky Longley ◽  
Angela Loyse ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Association Study ◽  
Cryptococcal Meningitis ◽  
Genome Wide Association Study ◽  
Ex Vivo ◽  
Genome Wide Association ◽  
Colony Stimulating Factor ◽  
Genome Wide ◽  
Immunodeficiency Virus ◽  
Stimulating Factor

Abstract Background Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%–10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. Methods We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). Results Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10–6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42–0.66; P = 5.96 × 10−8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. Conclusions This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.

scholarly journals Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus–1

2018 ◽  
Vol 69 (2) ◽  
pp. 295-305 ◽  
Author(s):  
Maia Lesosky ◽  
Molebogeng X Rangaka ◽  
Cara Pienaar ◽  
Anna K Coussens ◽  
Rene Goliath ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Controlled Trial ◽  
Interleukin 2 ◽  
Diagnostic Tools ◽  
Control Group ◽  
Plasma Biomarkers ◽  
Network Analyses ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Background The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1–infected individuals are likely to progress to active disease is unknown. Methods Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1–infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. Results Unstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC > 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. Conclusions Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.

scholarly journals A Randomized, Double-blinded, Placebo-controlled Trial of Sitagliptin for Reducing Inflammation and Immune Activation in Treated and Suppressed Human Immunodeficiency Virus Infection

2018 ◽  
Vol 69 (7) ◽  
pp. 1165-1172 ◽  
Author(s):  
Michael P Dubé ◽  
Ellen S Chan ◽  
Jordan E Lake ◽  
Brett Williams ◽  
Jennifer Kinslow ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
Controlled Trial ◽  
Multicenter Trial ◽  
Immune Markers ◽  
Dipeptidyl Peptidase 4 ◽  
Immunodeficiency Virus ◽  
Regulatory Effects ◽  
Double Blinded ◽  
Hispanic White

Abstract Background Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. Methods Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/μL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15–16. Results Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/μL. At week 15–16, there was no difference in sCD14 change between the 2 arms (P = .69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, –57% to –35%) at week 15 (P < .001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. Conclusions Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. Clinical Trials Registration NCT01426438.

scholarly journals CD34+ hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1281-1286 ◽  
Author(s):  
D von Laer ◽  
FT Hufert ◽  
TE Fenner ◽  
S Schwander ◽  
M Dietrich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Aids Patients ◽  
Proviral Dna ◽  
Two Samples ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Hematologic abnormalities occur in the majority of patients with acquired immunodeficiency syndrome (AIDS). Infection of the hematopoietic progenitor cells has been proposed as a potential explanation. In this study, different bone marrow cell populations, including the CD34+ hematopoietic progenitor cells, were purified by a fluorescence-activated cell sorter (FACS) and analyzed for the presence of human immunodeficiency virus-1 (HIV-1) proviral DNA using the polymerase chain reaction. A group of 14 patients with AIDS or AIDS- related complex (ARC) was studied (11 with peripheral blood cytopenias). The CD4+ helper cells in the bone marrow were found positive for HIV-1 DNA in all patients. In contrast, CD34+ progenitor cells were positive in only one patient. Two monocyte samples and two samples of CD4-/CD34- lymphocytes/blasts (mainly B and CD8 lymphocytes) were positive. Proviral DNA could not be detected in granulocytes. FACS analysis showed that the percentage of CD34+ hematopoietic progenitor cells was not altered in the bone marrow of AIDS patients in comparison with the HIV-1 seronegative controls. In contrast, the number of CD4+ lymphocytes was markedly reduced in the bone marrow of AIDS patients. These results show that the hematologic abnormalities in AIDS patients are neither explained by direct infection of the hematopoietic progenitor cells with HIV-1 nor by a depletion of progenitor cells.

scholarly journals Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

2005 ◽  
Vol 49 (8) ◽  
pp. 3361-3366 ◽  
Author(s):  
Vincent Jullien ◽  
Jean-Marc Tréluyer ◽  
Elisabeth Rey ◽  
Patrick Jaffray ◽  
Anne Krivine ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Clearance ◽  
Distribution Volume ◽  
Tubular Dysfunction ◽  
Concomitant Treatment ◽  
Time Curve ◽  
Mixed Effects Modeling ◽  
Highly Active ◽  
Immunodeficiency Virus

ABSTRACT The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc /F), peripheral distribution volume (Vp /F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 534 liters, 1,530 liters, 144 liters/h and 90.9 liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/SCR) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC0-24). In patients without tubular dysfunction, AUC0-24 values markedly decreased from 6.7 to 1.4 mg · h/liter for BW/SCR increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/SCR should be further evaluated.

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