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Sarah Palmer,
Valerie Boltz,
Frank Maldarelli,
Mary Kearney,
Elias K Halvas,
Diane Rock,
Judith Falloon, Richard T Davey,
Robin L Dewar,
Julia A Metcalf,
John W Mellors,
John M Coffin
[show abstract]
[hide abstract]
ABSTRACT: Understanding the selection and decay of drug-resistant HIV-1 variants is important for designing optimal antiretroviral therapy.
To develop a high-throughput, real-time reverse transcriptase (RT) polymerase chain reaction (PCR) assay to quantify non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants K103N (AAT or AAC alleles) at frequencies as low as 0.1%, and to apply this to monitor these variants before, during, and after NNRTI therapy.
HIV-1 RNA in longitudinal plasma samples obtained from patients starting and stopping NNRTI therapy was converted to cDNA and the target sequence region amplified and quantified by real-time PCR. Approximately 10 copies/reaction provided a template for a second round of PCR using primers that discriminated between the mutant and wild-type alleles. Amplification specificity was confirmed by thermal denaturation analysis.
Frequencies of 103N similar to assay background (0.029%) were observed in longitudinal samples from 9 of 12 treatment-naive patients; three patients had transient increases in 103N frequency to a range of 0.21-0.48%, which was 7-16.5 times assay background. Analysis of longitudinal plasma samples from six NNRTI-experienced patients showed three patterns: persistence of 103N variants after stopping NNRTI therapy, codon switching of 103N between AAC and AAT during NNRTI therapy, and decay of 103N variants to below assay background after cessation of NNRTI therapy.
Allele-specific RT-PCR quantified the emergence and decay of drug-resistant variants in patients over a broad range of frequencies (0.1-100%). The rate of decay of K103N variants after stopping NNRTI therapy was highly variable.
AIDS 04/2006; 20(5):701-10. · 6.24 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Intermittent administration of interleukin (IL)-2 to HIV infected patients leads to CD4 T-cell expansions that are associated with decreased CD4 T-cell turnover. IL-2 is under evaluation in antiretroviral therapy (ART) interruption studies, but it is unclear how the emergence of viremia may affect CD4 expansions.
CD4 T-cell responses were evaluated in 27 HIV infected patients on long-term intermittent IL-2 therapy who underwent ART interruption immediately after an IL-2 cycle ('IL-2/off') and compared with responses from a previous IL-2 cycle while on continuous ART ('IL-2/on'). Immunophenotypic analysis, including intracellular Ki67 staining, of cryopreserved peripheral blood mononuclear cells was performed.
CD4 T-cell increases, in naive and central memory CD4 T-cell subsets, were observed in the IL-2/on (106 and 327 cells/microl, respectively) and IL-2/off (84 and 184 cells/microl, respectively) cycles 1 month following IL-2 administration. These increases were greater during the IL-2/on cycle (P = 0.05, P = 0.01, respectively). In both cycles, the change in CD4 T-cell count correlated with the change in CD4/CD25 T cells. In the IL-2/off cycle, the change in the proportion of CD4 T cells expressing Ki67 was associated with both the changes in viral load (r = 0.64, P = 0.001) and the changes in CD4 T cells (r = -0.56, P = 0.01).
IL-2 administration followed by ART interruption led to significant, although blunted, CD4 T-cell increases. IL-2 induced CD4 T-cell increases in the setting of emergent viremia were associated with decreased CD4 T-cell activation that counteracted the viremia-induced increases in CD4 T-cell activation.
AIDS 03/2006; 20(3):361-9. · 6.24 Impact Factor
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Joseph A Kovacs,
Richard A Lempicki,
Igor A Sidorov,
Joseph W Adelsberger,
Irini Sereti,
William Sachau,
Grace Kelly,
Julia A Metcalf, Richard T Davey,
Judith Falloon, [......],
Douglas A Hosack,
Marjorie Bosche,
Haleem J Issaq,
Stephen D Fox,
Susan Leitman,
Michael W Baseler,
Henry Masur,
Michele Di Mascio,
Dimiter S Dimitrov,
H Clifford Lane
[show abstract]
[hide abstract]
ABSTRACT: HIV infection leads to decreases in the number of CD4 T lymphocytes and an increased risk for opportunistic infections and neoplasms. The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with 2H-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-lives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27+CD45RO-) as well as central memory (CD27+CD45RO+) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens.
Journal of Clinical Investigation 09/2005; 115(8):2139-48. · 15.39 Impact Factor
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Irini Sereti,
Hiromi Imamichi,
Ven Natarajan,
Tomozumi Imamichi,
Meena S Ramchandani,
Yunden Badralmaa,
Steve C Berg,
Julia A Metcalf,
Barbara K Hahn,
Jean M Shen,
April Powers, Richard T Davey,
Joseph A Kovacs,
Ethan M Shevach,
H Clifford Lane
[show abstract]
[hide abstract]
ABSTRACT: Administration of IL-2 to HIV-infected patients leads to expansion of a unique subset of CD4CD45ROCD25 cells. In this study, the origin, clonality, and function of these cells were investigated. Analysis of TCR excision circles revealed that the CD4CD45ROCD25 cells were the product of peripheral expansion but remained polyclonal as determined by TCR repertoire analysis. Phenotypically, these cells were distinct from naturally occurring Tregs; they exhibited intermediate features, between those of memory and naive cells, and had lower susceptibility to apoptosis than CD45ROCD25 or memory T cells. Studies of intracellular cytokine production and proliferation revealed that cytokine-expanded naive CD25 cells had low IL-2 production and required costimulation for proliferation. Despite elevated expression of forkhead transcription factor P3 (foxP3), they exerted only weak suppression compared with CD45ROCD25 cells (Tregs). In summary, in vivo IL-2 administration to HIV-infected patients leads to peripheral expansion of a population of long-lived CD4CD45ROCD25 cells that express high levels of foxP3 but exert weak suppressive function. These CD4CD25 cytokine-expanded naive cells, distinct from antigen-triggered cells and Tregs, play a role in the maintenance of a state of low turnover and sustained expansion of the CD4 T cell pool.
Journal of Clinical Investigation 08/2005; 115(7):1839-47. · 15.39 Impact Factor
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Sarah Palmer,
Mary Kearney,
Frank Maldarelli,
Elias K Halvas,
Christian J Bixby,
Holly Bazmi,
Diane Rock,
Judith Falloon, Richard T Davey,
Robin L Dewar,
Julia A Metcalf,
Scott Hammer,
John W Mellors,
John M Coffin
[show abstract]
[hide abstract]
ABSTRACT: To investigate the extent to which drug resistance mutations are missed by standard genotyping methods, we analyzed the same plasma samples from 26 patients with suspected multidrug-resistant human immunodeficiency virus type 1 by using a newly developed single-genome sequencing technique and compared it to standard genotype analysis. Plasma samples were obtained from patients with prior exposure to at least two antiretroviral drug classes and who were on a failing antiretroviral regimen. Standard genotypes were obtained by reverse transcriptase (RT)-PCR and sequencing of the bulk PCR product. For single-genome sequencing, cDNA derived from plasma RNA was serially diluted to 1 copy per reaction, and a region encompassing p6, protease, and a portion of RT was amplified and sequenced. Sequences from 15 to 46 single viral genomes were obtained from each plasma sample. Drug resistance mutations identified by single-genome sequencing were not detected by standard genotype analysis in 24 of the 26 patients studied. Mutations present in less than 10% of single genomes were almost never detected in standard genotypes (1 of 86). Similarly, mutations present in 10 to 35% of single genomes were detected only 25% of the time in standard genotypes. For example, in one patient, 10 mutations identified by single-genome sequencing and conferring resistance to protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were not detected by standard genotyping methods. Each of these mutations was present in 5 to 20% of the 20 genomes analyzed; 15% of the genomes in this sample contained linked PI mutations, none of which were present in the standard genotype. In another patient sample, 33% of genomes contained five linked NNRTI resistance mutations, none of which were detected by standard genotype analysis. These findings illustrate the inadequacy of the standard genotype for detecting low-frequency drug resistance mutations. In addition to having greater sensitivity, single-genome sequencing identifies linked mutations that confer high-level drug resistance. Such linkage cannot be detected by standard genotype analysis.
Journal of Clinical Microbiology 02/2005; 43(1):406-13. · 4.15 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Interleukin-2 (IL-2) is a cytokine that regulates the proliferation and differentiation of lymphocytes, and is currently used clinically in the treatment of assorted malignancies. Additionally, IL-2 is being actively investigated in clinical trials for treatment of human immunodeficiency virus (HIV) infection. Patients treated with IL-2 are susceptible to autoimmune thyroid disease (AITD), presenting as thyroiditis, which leads to either thyrotoxicosis or hypothyroidism, if not correctly and promptly identified and treated. IL-2-induced hypothyroidism can also sometimes follow a thyrotoxic phase. However, the development of Graves' disease (GD) in this clinical setting has not been reported to date. Here, we report the case of a 39-year-old HIV-infected man in whom GD developed after IL-2 therapy. We correlated the immunologic parameters pertinent to the patient's HIV infection status with clinical, hormonal, and serologic evidence of GD during its emergence. This revealed an association between peripheral blood cell numbers of specific lymphocyte subpopulations (CD4(+), CD3(+)CD25(+), and naïve T-cells) and serum levels of markers for AITD (free thyroxine [T(4)] and thyroid-stimulating immunoglobulin). Interestingly, no association was found between natural killer (NK) cell numbers and AITD markers. The immunopathogenesis of GD in this patient may be similar to that hypothesized for the GD that occurs in immune-reconstituted patients after combination antiretroviral therapy. From a practical standpoint, we propose that patients who have received or are receiving treatment with IL-2 who show signs of hyperthyroidism need to be carefully evaluated for GD.
Thyroid 01/2005; 14(12):1097-102. · 4.79 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Interleukin-2 administration induces CD4 T cell expansion in HIV-infected patients, however, toxicity can limit dosing. BAY 50-4798 is a recombinant IL-2 analog with >1000-fold specificity for the high-affinity IL-2 receptor. The effects of this compound on unstimulated human PBMC were evaluated. PBMC from HIV(-) and HIV(+) donors were cultured in vitro with incremental doses of BAY 50-4798 or aldesleukin. CD25 expression and proliferation were evaluated with flow cytometry. Cytokine levels were measured by ELISA in culture supernatants. BAY 50-4798 induced dose-dependent increases in CD25 expression and proliferation of T cells, NK, and B cells and showed selectivity for CD4 T cells expressing CD25. Induction of pro-inflammatory cytokines was also dose-dependent and was observed at the concentrations of BAY 50-4798 with the highest biologic activity. These data suggest that BAY 50-4798 can induce proliferation of unstimulated T cells but loss of T cell selectivity and induction of pro-inflammatory cytokines occur at concentrations exerting the highest biologic activity.
Clinical Immunology 12/2004; 113(3):248-55. · 4.05 Impact Factor
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Irini Sereti,
Kara B Anthony,
Hector Martinez-Wilson,
Richard Lempicki,
Joseph Adelsberger,
Julia A Metcalf,
Claire W Hallahan,
Dean Follmann, Richard T Davey,
Joseph A Kovacs,
H Clifford Lane
[show abstract]
[hide abstract]
ABSTRACT: Administration of interleukin 2 (IL-2) leads to selective and sustained CD4+ T-cell expansions in patients infected with HIV. It has been hypothesized that persistent CD4+ T-cell proliferation is the primary mechanism maintaining these expansions. T-cell proliferation was studied by ex vivo bromodeoxyuridine (BrdU) incorporation and intracellular Ki67 staining in HIV-infected patients treated with antiretroviral therapy (ART) with or without IL-2. In contrast to the tested hypothesis, HIV-infected patients treated with IL-2 had lower CD4+ T-cell proliferation compared to patients treated with ART alone. Independently of viral load changes, administration of IL-2 led to a decrease in basal CD4+ T-cell proliferation. Total numbers of CD4+ T cells with naive and recall, but not effector, memory phenotype were increased. The degree of CD4+ T-cell expansion correlated with the decreases in proliferation and a strong association was seen between these decreases and the expansion of the CD4+/CD25+ subset. Intermittent IL-2 in HIV-infected patients leads to expansions of CD4+/CD25+ T cells with naive and recall memory phenotypes that strongly correlate with decreases in proliferation. These data suggest that decreased T-cell proliferation is central in the CD4+ T-cell expansions induced by IL-2.
Blood 09/2004; 104(3):775-80. · 9.90 Impact Factor
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Roberto C Arduino,
Esteban C Nannini,
Maria Rodriguez-Barradas,
Shannon Schrader,
Marcelo Losso,
Kiat Ruxrungtham,
Maria C Allende,
Sean Emery,
Lisa Fosdick,
James Neaton,
Jorge A Tavel, Richard T Davey,
H Clifford Lane
[show abstract]
[hide abstract]
ABSTRACT: In advance of a large clinical end point trial evaluating the effectiveness of subcutaneous interleukin 2 (scIL-2) for treatment of patients with human immunodeficiency virus (HIV) infection, 3 identically designed Vanguard trials were conducted in Buenos Aires, Argentina; Bangkok, Thailand; and Houston, Texas. To more precisely quantitate the effect on CD4 cell response of 3 different doses of scIL-2 that were administered twice daily for 5 days every 8 weeks, the results of these 3 trials were pooled in a meta-analysis.
Two hundred eighteen HIV-1-infected subjects who were receiving antiretroviral therapy and who had a baseline CD4 cell count of > or =350 cells/mm3 were consecutively randomized to receive scIL-2 at a dose of 1.5 mIU (n=36) or a control regimen (n=36); or scIL-2 at a dose of 4.5 mIU (n=36) or a control regimen (n=36); or scIL-2 at a dose of 7.5 mIU (n=37) or a control regimen (n=37). After completion of 3 cycles of therapy, the subjects were enrolled in an extension phase (months 6-12). Subjects were encouraged to receive additional cycles of scIL-2 to maintain a CD4 cell count of more than twice the baseline count or >1000 cells/mm3.
After completion of 3 cycles of scIL-2, the mean CD4 cell count changes from baseline (calculated as changes from baseline in a scIL-2 group minus changes from baseline in its contemporaneous control group) were 67 (P=.14), 339 (P<.0001), and 605 cells/mm3 (P<.0001) for the 1.5, 4.5, and 7.5 mIU dose groups, respectively (P<.0001 for differences among dose groups). Between months 6 and 12, a total of 78%, 39%, and 32% of subjects assigned to the 1.5, 4.5, and 7.5 mIU dose groups, respectively, needed at least 1 additional cycle to achieve the CD4 cell count goal. At 12 months, the differences in the mean change in CD4 cell count from baseline between each scIL-2 dose group and its contemporaneous control group were 184, 369, and 432 cells/mm3, respectively (P=.01 for differences among dose groups).
Although CD4 cell count increases were seen in all 3 dose groups, higher scIL-2 doses resulted in greater CD4 cell count changes after 6 months, compared with control groups.
Clinical Infectious Diseases 07/2004; 39(1):115-22. · 9.15 Impact Factor
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Mark Dybul,
Elizabeth Nies-Kraske,
Robin Dewar,
Frank Maldarelli,
Claire W Hallahan,
Marybeth Daucher,
Stephen C Piscitelli,
Linda Ehler,
Ann Weigand,
Sarah Palmer,
Julia A Metcalf, Richard T Davey,
Diane M Rock Kress,
April Powers,
Ingrid Beck,
Lisa Frenkel,
Michael Baseler,
John Coffin,
Anthony S Fauci
[show abstract]
[hide abstract]
ABSTRACT: We previously demonstrated that short-cycle structured intermittent therapy (SIT; 7 days without therapy followed by 7 days with antiretroviral therapy [ART]) with a ritonavir-boosted, indinavir-based, twice-daily regimen maintained suppression of plasma HIV viremia while reducing serum levels of lipids. Adherence to such a regimen may be problematic for certain patients.
Eight patients with a history of receiving combination ART that maintained suppression of plasma HIV RNA to <50 copies/mL received a once-daily SIT regimen of didanosine, lamivudine, and efavirenz.
For 7 patients, suppression of plasma HIV RNA to <50 copies/mL was maintained for 60-84 weeks. Four patients with adequate samples had no evidence for an increase in plasma viremia for up to 72 weeks, by use of an assay with a limit of detection of <1 copy/mL. The lack of rebound viremia may be the result of the persistence of efavirenz in plasma on day 7 of the no-therapy period, as was detected in 7 of 7 patients. There was no significant change in CD4(+) T cell counts or serum hepatic transaminase or lipid levels.
A once-daily short-cycle SIT regimen maintained suppression of plasma HIV RNA while preserving CD4(+) T cell counts. Such a regimen may have importance in resource-limited settings where the monetary cost of continuous ART is prohibitive.
The Journal of Infectious Diseases 07/2004; 189(11):1974-82. · 6.41 Impact Factor
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ABSTRACT: Studies establishing that intermittent subcutaneous interleukin-2 (IL-2) therapy can lead to substantial CD4 cell increases in many HIV-infected patients have generally been of limited duration. We studied 77 patients participating in active longitudinal studies of subcutaneous IL-2 therapy at our center in order to determine the long-term feasibility of this approach. Following initial induction, patients in each trial were eligible to receive intermittent 5-day cycles of subcutaneous IL-2 treatment at individualized doses and frequencies capable of maintaining CD4 counts at postinduction levels. The mean duration of study participation to date is 5.9 years (range, 1.0-9.3 years). Mean baseline CD4 cell count and CD4 percent values of 0.521 x 10(9)/L (521 cells/microL) and 27% have risen to 1.005 x 10(9)/L (1005 cells/microL) and 38%, respectively, at 90 months. The mean number of subcutaneous IL-2 cycles required to achieve and maintain these increases was 10 cycles (range, 3-29 cycles), and the current mean interval of cycling required to maintain these elevations is 39 months (median, 35 months; range, 2-91 months). We conclude that subcutaneous IL-2 therapy is capable of maintaining CD4 cell increases for an extended period using a remarkably low frequency of intermittent cycling. These observations may contribute to patients' acceptance of subcutaneous IL-2 as a favorable long-term treatment strategy.
Blood 06/2004; 103(9):3282-6. · 9.90 Impact Factor
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Christiana Iyasere,
John C Tilton,
Alison J Johnson,
Souheil Younes,
Bader Yassine-Diab,
Rafick-Pierre Sekaly,
William W Kwok,
Stephen A Migueles,
Alisha C Laborico,
W Lesley Shupert,
Claire W Hallahan, Richard T Davey,
Mark Dybul,
Susan Vogel,
Julia Metcalf,
Mark Connors
[show abstract]
[hide abstract]
ABSTRACT: Virus-specific CD4(+) T-cell function is thought to play a central role in induction and maintenance of effective CD8(+) T-cell responses in experimental animals or humans. However, the reasons that diminished proliferation of human immunodeficiency virus (HIV)-specific CD4(+) T cells is observed in the majority of infected patients and the role of these diminished responses in the loss of control of replication during the chronic phase of HIV infection remain incompletely understood. In a cohort of 15 patients that were selected for particularly strong HIV-specific CD4(+) T-cell responses, the effects of viremia on these responses were explored. Restriction of HIV replication was not observed during one to eight interruptions of antiretroviral therapy in the majority of patients (12 of 15). In each case, proliferative responses to HIV antigens were rapidly inhibited during viremia. The frequencies of cells that produce IFN-gamma in response to Gag, Pol, and Nef peptide pools were maintained during an interruption of therapy. In a subset of patients with elevated frequencies of interleukin-2 (IL-2)-producing cells, IL-2 production in response to HIV antigens was diminished during viremia. Addition of exogenous IL-2 was sufficient to rescue in vitro proliferation of DR0101 class II Gag or Pol tetramer(+) or total-Gag-specific CD4(+) T cells. These observations suggest that, during viremia, diminished in vitro proliferation of HIV-specific CD4(+) T cells is likely related to diminished IL-2 production. These results also suggest that relatively high frequencies of HIV-specific CD4(+) T cells persist in the peripheral blood during viremia, are not replicatively senescent, and proliferate when IL-2 is provided exogenously.
Journal of Virology 11/2003; 77(20):10900-9. · 5.40 Impact Factor
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Mark Dybul,
Elizabeth Nies-Kraske,
Marybeth Daucher,
Kurt Hertogs,
Claire W Hallahan,
Gyorgy Csako,
Christian Yoder,
Linda Ehler,
Peter A Sklar,
Michael Belson,
Bertha Hidalgo,
Julia A Metcalf, Richard T Davey,
Diane M Rock Kress,
April Powers,
Anthony S Fauci
[show abstract]
[hide abstract]
ABSTRACT: We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4(+) or CD8(+) T cell counts or the percentage of cells that were CD4(+)CD25(+), CD8(+)CD25(+), or CD4(+)DR(+), patients who received SIT had a significantly higher percentage of CD8(+)CD38(+) and CD8(+)DR(+) cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cycle SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters.
The Journal of Infectious Diseases 09/2003; 188(3):388-96. · 6.41 Impact Factor
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Jorge A Tavel,
Irini Sereti,
Robert E Walker,
Barbara Hahn,
Joseph A Kovacs,
Shyla Jagannatha, Richard T Davey,
Judith Falloon,
Michael A Polis,
Henry Masur,
Julia A Metcalf,
Randy Stevens,
Adam Rupert,
Michael Baseler,
H Clifford Lane
[show abstract]
[hide abstract]
ABSTRACT: Intermittent administration of interleukin (IL)-2 produces significant and sustained increases in CD4(+) T lymphocyte count in human immunodeficiency virus (HIV)-infected subjects but can be associated with dose-limiting toxicities. The primary objective of this study was to determine whether concomitant administration of prednisone could decrease these toxicities. HIV-seropositive adults receiving highly active antiretroviral therapy (HAART) were randomized to receive either (1) intermittent subcutaneous IL-2 and placebo, (2) intermittent subcutaneous IL-2 and prednisone, (3) intermittent prednisone, or (4) intermittent placebo. Prednisone decreased levels of proinflammatory cytokines during IL-2 cycles but, despite induction of expression of CD25, blunted increases in IL-2-associated CD4(+) T lymphocyte count. Whereas intermittent administration of IL-2 reduced basal proliferation of CD4(+) T cells, this effect was inhibited by prednisone, suggesting that prednisone potentially interferes with IL-2's long-term effects on survival of T lymphocytes.
The Journal of Infectious Diseases 09/2003; 188(4):531-6. · 6.41 Impact Factor
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Michael A Polis,
Daniel L Suzman,
Christian P Yoder,
Jean M Shen,
JoAnn M Mican,
Robin L Dewar,
Julia A Metcalf,
Judith Falloon, Richard T Davey,
Joseph A Kovacs,
Mark B Feinberg,
Henry Masur,
Stephen C Piscitelli
[show abstract]
[hide abstract]
ABSTRACT: To determine the longitudinal response of HIV in the cerebrospinal fluid (CSF) to highly active antiretroviral therapy (HAART) and to investigate the levels of indinavir penetrating into the CSF.
Open study of HIV-infected subjects naive to therapy with protease inhibitors.
Tertiary care referral center.
Twenty-five participants were begun on indinavir, nevirapine, zidovudine, and lamivudine.
Lumbar punctures were performed prior to therapy and 2 and 6 months after beginning therapy. Plasma and CSF were assayed for routine cell counts, chemistries, HIV load and indinavir levels.
Twenty-two subjects had CSF HIV RNA level data available at all three time points, three others at baseline and 2 months. At month 2 of therapy, nine of 25 (36%) subjects had CSF HIV RNA levels > 50 HIV RNA copies/ml. By 6 months, all 22 subjects had CSF HIV RNA levels < 50 HIV RNA copies/ml. CSF white blood cell counts fell from a baseline mean of 5.3 x 10(6)/l to 1.9 x 10(6)/l (P = 0.013) at 6 months. Plasma indinavir levels declined rapidly while CSF levels remained stable throughout the 8-h dosing interval. The median CSF indinavir level was 71 ng/ml, approximating the upper limit of the 95% inhibitory concentration for indinavir against HIV-1.
CSF HIV RNA levels cannot be expected to fall below 50 HIV RNA copies/ml even after 2 months of therapy on HAART. Prolonged therapy may be required to suppress HIV levels within the central nervous system.
AIDS 05/2003; 17(8):1167-72. · 6.24 Impact Factor
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Mark Dybul,
Marybeth Daucher,
Mark A Jensen,
Claire W Hallahan,
Tae-Wook Chun,
Michael Belson,
Bertha Hidalgo,
David C Nickle,
Christian Yoder,
Julia A Metcalf, Richard T Davey,
Linda Ehler,
Diane Kress-Rock,
Elizabeth Nies-Kraske,
Shuying Liu,
James I Mullins,
Anthony S Fauci
[show abstract]
[hide abstract]
ABSTRACT: Various strategies of interrupting highly active antiretroviral therapy (HAART) are being investigated for the treatment of human immunodeficiency virus (HIV) infection. Interruptions of greater than 2 weeks frequently result in rebound of plasma HIV RNA. In order to discern changes in the viral population that might occur during cycles of treatment interruption, we evaluated the homology of HIV-1 envelope gene sequences over time in 12 patients who received four to seven cycles of 4 weeks off HAART followed by 8 weeks on HAART by using the heteroduplex tracking assay and novel statistical tools. HIV populations in 9 of 12 patients diverged from those found in the first cycle in at least one subsequent cycle. The substantial genetic changes noted in HIV env did not correlate with increased or decreased log changes in levels of plasma HIV RNA (P > 0.5). Thus, genetic changes in HIV env itself did not contribute in a systematic way to changes in levels of plasma viremia from cycle to cycle of treatment interruption. In addition, the data suggest that there may be multiple compartments contributing to the rebound of plasma viremia and to viral diversity from cycle to cycle of intermittent therapy.
Journal of Virology 03/2003; 77(5):3229-37. · 5.40 Impact Factor
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[show abstract]
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ABSTRACT: The long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV(+)) patients receiving highly active antiretroviral therapy (HAART), and HIV(+) patients receiving HAART and intermittent IL-2. Whole-blood immunophenotyping was performed to study expression of the IL-2 receptor chains on T lymphocytes and natural killer cells and to further characterize CD4(+)/CD25(+) T cells. Increased CD25 expression, especially in CD4(+) T cells but also in CD8(+) T cells, without increases in expression of the beta and gamma chains of the IL-2 receptor was detected in the IL-2 group. Up to 79% of naive CD4(+) T cells (median, 61%) from patients in the IL-2 group expressed CD25, and the number of naive CD4(+)/CD25(+) T cells correlated positively with both the total and naive CD4(+) T-cell counts. A discrete population of CD45 double intermediate RA(+)/RO(+) CD4(+) cells was also preferentially expanded in the IL-2 group, and the number of these cells strongly correlated with the total CD4(+) count. Despite increases in CD25 expression, T lymphocytes from patients treated with IL-2 did not have increased expression of early (CD69) or late (CD95) activation markers or evidence of recent proliferation (Ki67). Both CD4(+)/CD25(+) and CD4(+)/CD25(-) cells from IL-2-treated HIV(+) patients proliferated in response to mitogens, specific antigens, and T-cell-receptor-mediated stimuli. Thus, intermittent administration of IL-2 in HIV(+) patients leads to preferential expansion of a unique subset of CD4(+) T cells that may represent a critical population in T-cell homeostasis.
Blood 10/2002; 100(6):2159-67. · 9.90 Impact Factor
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Kirk D Miller,
Henry Masur,
Elizabeth C Jones,
Galen O Joe,
Margaret E Rick,
Grace G Kelly,
JoAnn M Mican,
Shuying Liu,
Lynn H Gerber,
William C Blackwelder,
Judith Falloon, Richard T Davey,
Michael A Polis,
Robert E Walker,
H Clifford Lane,
Joseph A Kovacs
[show abstract]
[hide abstract]
ABSTRACT: Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing.
To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis.
Survey and comparison study.
The Clinical Center of the U.S. National Institutes of Health.
339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999.
Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state.
Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies.
Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.
Annals of internal medicine 08/2002; 137(1):17-25. · 16.73 Impact Factor
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ABSTRACT: The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3 who were receiving antiretroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4+ cell counts that were twice the baseline value or > or = 1,000/mm3. The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4+ cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of <50 copies/mL at 12 months (p =.55), time to viral load of > or = 50 copies/mL for patients who had baseline viral loads of <50 copies/mL (p =.35), and change in viral load from baseline for patients who had viral loads of > or = 50 copies/mL at baseline (p =.63). At each follow-up visit, the change in CD4+ cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm3 at month 12 (95% confidence interval, 207-295; p <.0001). No unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date.
JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2002; 29(3):221-31. · 4.43 Impact Factor
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Mark Dybul,
Bertha Hidalgo,
Tae-Wook Chun,
Michael Belson,
Stephen A Migueles,
Jesse S Justement,
Betsey Herpin,
Cheryl Perry,
Claire W Hallahan, Richard T Davey,
Julia A Metcalf,
Mark Connors,
Anthony S Fauci
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ABSTRACT: Highly active antiretroviral therapy (HAART) initiated during acute human immunodeficiency virus (HIV) infection may preserve HIV-specific CD4+ T cell responses that are thought to enhance HIV-specific CD8+ T cell function. The present pilot study was designed to determine whether preserved HIV-specific immune responses are augmented by the administration of the immunomodulatory agent interleukin (IL)-2. Nine persons recently (<6 months) infected with HIV were randomized to receive HAART alone or HAART plus 3 cycles of intermittent IL-2 during a 12-month period. Although HAART plus IL-2 significantly increased counts of total and naive CD4+ T cells, compared with HAART alone, there was no increase in CD4+ or CD8+ HIV-specific immune responses. In addition, adjuvant IL-2 therapy did not reduce the pool of HIV-infected resting CD4+ T cells. Thus, although intermittent IL-2 plus HAART quantitatively increased CD4+ T cells, this increase was not selective for HIV-specific CD4+ or CD8+ T cell responses in recently infected persons.
The Journal of Infectious Diseases 01/2002; 185(1):61-8. · 6.41 Impact Factor
