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Biomedical subjects

M S Saag

Publications and source records attributed to M S Saag.

At least 37 records · Page 2Linked to original sources
PubMed1999

Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients.

This open-label, multicenter trial evaluated the efficacy and safety of a new oral solution formulation of itraconazole in HIV+/AIDS patients with fluconazole-refractory oropharyngeal candidiasis. Seventy-four HIV+/AIDS patients with mycologically confirmed oropharyngeal candidiasis who failed fluconazole therapy (200 mg/day) were treated with 100 mg of itraconazole oral solution administered twice daily (200 mg/day) for 14 days. Patients who demonstrated an incomplete response to treatment were treated for an additional 14 days (28 days total). Clinical responders were eligible for participation in a separate 6-month maintenance protocol. If they declined further treatment, responders were monitored for 6 weeks posttreatment. The primary efficacy parameter was clinical response (i.e., no lesions or symptoms) at end of treatment. Fungal cultures were performed at baseline and at the end of treatment. Among the 74 patients who had mycologically confirmed, fluconazole-unresponsive, oropharyngeal candidiasis at baseline, 41 (55%) achieved a clinical response by day 28. The median time to response was 7 days (range, 7 to 28 days). Candida albicans was the most common pathogen isolated, either alone (62%) or in combination with another Candida species (31%). All 22 patients who entered the optional, off-therapy, 6-week follow-up phase relapsed; mean time to relapse was 13 days. Itraconazole oral solution was well-tolerated; adverse events were predominantly gastrointestinal disturbances. This trial demonstrates that itraconazole oral solution is a useful therapy in the treatment of HIV-infected patients with fluconazole-refractory oropharyngeal candidiasis.

AIDS-Related Opportunistic Infections↗
PubMed1999

Predictors of optimal virological response to potent antiretroviral therapy.

BACKGROUND: Current potent antiretroviral therapy (using a protease inhibitor and two nucleoside reverse transcriptase inhibitors) produces a durable suppression of HIV replication in less than 75% of treated patients. Identification of predictors of successful therapy might allow the development of improved strategies to increase response rates. METHODS: We analyzed retrospectively the results from a multicenter, randomized, double-blind Phase III study of combination anti-HIV therapy with nelfinavir, zidovudine, and lamivudine to evaluate the relationship between virological response over 48 weeks of treatment to variables which could potentially serve as early predictors of long-term response. The goal was to produce long-term suppression of viral load to sensitive (<400 copies HIV RNA/ml) and ultrasensitive (<50 copies HIV RNA/ml) limits of quantification with the Amplicor PCR assay. FINDINGS: Baseline viral load, the change in viral load over the first 4 weeks of treatment, the 2 h post-dose nelfinavir levels and the time to respond to HIV RNA levels of <400 copies/ml and <50 copies/ml have the best predictive value in determining response and response duration. Patients who achieved very low viral nadirs (<50 copies HIV RNA/ml) had significantly longer responses than those who achieved nadirs of 50-400 copies HIV RNA/ml. INTERPRETATION: Parameters that can be measured easily at baseline or early after therapy is started can identify patients at high risk of failure with standard treatment. Such patients may be candidates for more aggressive therapy or for alternative strategies designed to improve outcome. In addition, these results support the use of ultra-sensitive HIV RNA assays to predict long-term outcome of anti-HIV therapy.

Adult↗
PubMed1999

Correlation between circulating stromal cell-derived factor 1 levels and CD4+ cell count in human immunodeficiency virus type 1-infected individuals.

Stromal cell-derived factor 1 (SDF-1) is the natural ligand that recognizes CXCR4, which also serves as a coreceptor for some strains of HIV-1. In this study, we explored SDF-1 blood levels among HIV-1-infected individuals exhibiting a wide range of CD4+ cell counts. Plasma or serum concentrations of SDF-1 protein were measured by ELISA in samples from 31 HIV-1-seronegative individuals and 79 HIV-1-infected subjects. Although SDF-1 protein levels were stable for months among seronegative individuals (mean intrasubject variation, 17%), the absolute values varied widely (0.28 to 106.5 ng/ml; mean, 25.6 ng/ml). In HIV-1-infected subjects, there was a direct correlation between SDF-1 level and CD4+ cell count. Subjects with fewer than 50 CD4+ cells per cubic microliter of blood had significantly lower mean SDF-1 levels (+/-SD) than did either HIV-1-infected subjects with higher CD4+ cell counts or uninfected controls: CD4+ cell count <50, mean SDF-1 level of 10.7+/-33.7, 50 < CD4+ cell count <200, mean SDF-1 level of 12.9+/-19.0, 200 < CD4+ cell count <500, mean SDF-1 level of 19.3+/-36.8; CD4+ cell count >500, mean SDF-1 level of 18.5+/-25.2; uninfected control mean SDF-1 level, 25.6+/-34.7. No significant change in SDF-1 level was detected after administration of antiretroviral therapy in nine subjects with advanced disease (mean intrasubject variation, 43%). Analysis of SDF-1 mRNA expression in lymph nodes from HIV-1-infected subjects at different disease stages revealed that the medullary cords contained stromal cells that express SDF-1 mRNA. This preliminary analysis suggests a possible link between lower SDF-1 levels and disease progression.

Adult↗
PubMed1999

Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA.

Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency <2/10(6) cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (<50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.

Antiviral Agents↗
PubMed1999

Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues.

Previous studies proposed a dynamic, steady-state relationship between HIV-mediated cell killing and T-cell proliferation, whereby highly active antiretroviral therapy (HAART) blocks viral replication and tips the balance toward CD4(+) cell repopulation. In this report, we have analyzed blood and lymph node tissues obtained concurrently from HIV-infected patients before and after initiation of HAART. Activated T cells were significantly more frequent in lymph node tissue compared with blood at both time points. Ten weeks after HAART, the absolute number of lymphocytes per excised lymph node decreased, whereas the number of lymphocytes in the blood tended to increase. The relative proportions of lymphoid subsets were not significantly changed in tissue or blood by HAART. The expression levels of mRNA for several proinflammatory cytokines (IFN-gamma, IL-1beta, IL-6, and macrophage inflammatory protein-1alpha) were lower after HAART. After therapy, the expression of VCAM-1 and ICAM-1 -- adhesion molecules known to mediate lymphocyte sequestration in lymphoid tissue -- was also dramatically reduced. These data provide evidence suggesting that initial increases in blood CD4(+) cell counts on HAART are due to redistribution and that this redistribution is mediated by resolution of the immune activation that had sequestered T cells within lymphoid tissues.

Adult↗
PubMed1999

Decrease of cytomegalovirus replication in human immunodeficiency virus infected-patients after treatment with highly active antiretroviral therapy.

Cytomegalovirus (CMV) viremia, as measured by a hybrid capture assay, was used to measure the effectiveness of "immune reconstitution" in human immunodeficiency virus (HIV)-infected subjects treated with highly active antiretroviral therapy (HAART). Of the 28 enrolled patients (mean age, 38 years), 86% were male and 68% were antiretrovirally naive. Of the 23 patients who returned for follow-up, baseline median characteristics were 4.1 log10 CMV DNA copies/106 white blood cells (WBCs), 5.1 log10 HIV RNA copies/mL, and 35 CD4 cells/mm3. After initiation of HAART, median log10 CMV DNA copies/106 WBCs at means of 33, 87, and 385 days were 4.0, 3.3, and 2.5, respectively. Median log10 HIV RNA levels declined from 5.1 to 1.7 at 385 days with a commensurate rise in median CD4 T cells to 166/mm3. Immune reconstitution secondary to HAART results in a significant and progressive decline in CMV viremia in the absence of specific anti-CMV therapy.

AIDS-Related Opportunistic Infections↗
PubMed1999

Evaluation of distinct blood lymphocyte populations in human immunodeficiency virus type 1-infected subjects in the absence or presence of effective therapy.

Virus reservoirs can persist in human immunodeficiency virus type 1 (HIV-1)-infected subjects despite effective plasma virus suppression. To compare viral dynamics in the absence and presence of antiretroviral therapy, blood mononuclear cells from 19 subjects with high plasma RNA levels and 18 subjects following prolonged virus suppression were examined, by use of in situ hybridization, to detect virus RNA expression before and after in vitro T cell activation. This approach reveals circulating lymphocytes expressing HIV-1 RNA before activation and an increase in cells with detectable HIV-1 RNA transcription after in vitro activation. The frequencies of these 2 cell populations are strongly correlated with plasma virus load and appear to be stable once a new steady state is established during therapy. The frequency of viral RNA-positive cells is equivalent to the frequency of cells that produce infectious virus. Thus, in HIV-1-infected subjects there are distinct virus reservoirs comprising both latent and replication-active cells.

Anti-HIV Agents↗
PubMed1999

A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04). Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults. Abacavir Phase 2 Clinical Team.

OBJECTIVES: To evaluate, over 12 weeks, the antiretroviral activity and safety of abacavir, used alone and in combination with zidovudine (ZDV), as treatment for HIV-1-infected subjects who had limited or no antiretroviral treatment. DESIGN: Seventy-nine HIV-1-infected subjects, with CD4 cell counts 200-500 x 10(6)/l and <12 weeks of previous treatment with ZDV were enrolled in a multicenter study. Subjects were randomly assigned to one of four cohorts receiving abacavir monotherapy for the first 4 weeks (200, 400, or 600 mg every 8 h daily, or 300 mg every 12 h daily) and, thereafter, combination therapy of abacavir with 600 mg ZDV or ZDV placebo, administered in a double-blind manner for an additional 8 weeks. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4+ cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities during the 12-week period and for 4 weeks post-treatment. RESULTS: Treatment with abacavir, alone or in combination with ZDV, produced marked decreases in plasma HIV-1 RNA loads and increases in CD4+ cell counts in all groups. At week 4, median plasma HIV-1 RNA loads decreased by 1.11-1.77 log10 copies/ml and median CD4+ cell counts increased by 63-111 x 10(6)/l in all groups. At week 12, median HIV-1 RNA loads decreased by 1.02-2.24 log10 copies/ml (abacavir monotherapy) and by 1.81-2.01 log10 copies/ml (abacavir-ZDV); median CD4+ cell counts increased by 79-195 x 10(6)/l (abacavir monotherapy) and by 93-142 x 10(6)/l (abacavir-ZDV). At week 12, the percentage of subjects who had plasma HIV-1 RNA levels below 400 and 40 copies/ml were 28 and 11%, respectively (abacavir monotherapy) and 69 and 22%, respectively (abacavir-ZDV). Eight subjects (10%) discontinued the study prematurely because of adverse events; nausea (n = 4) and hypersensitivity (n = 3) were the most common reasons for withdrawal. There were no deaths among the study subjects. CONCLUSIONS: In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To provide recommendations for antiretroviral therapy based on information available in mid-1998. PARTICIPANTS: An international panel of physicians with expertise in antiretroviral research and care of patients with human immunodeficiency virus (HIV) infection, first convened by the International AIDS Society-USA in December 1995. EVIDENCE: The panel reviewed available clinical and basic science study results (including phase 3 controlled trials; clinical, virologic, and immunologic end point data; data presented at research conferences; and studies of HIV pathophysiology); opinions of panel members were also considered. Recommendations were limited to drugs available in mid-1998. CONSENSUS PROCESS: Panel members monitor new clinical research reports and interim results. The full panel meets regularly to discuss how the new information may change treatment recommendations. Updated recommendations are developed through consensus of the entire panel at each stage of development. CONCLUSIONS: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection. A variety of combination regimens show potency, expanding choices for initial regimens for individual patients. Plasma HIV RNA assays with increased sensitivity are important in monitoring therapeutic response; however, more data are needed to determine precisely the HIV RNA levels that define treatment failure. Long-term adverse drug effects are beginning to emerge, requiring ongoing attention. Some issues regarding optimal long-term approaches to antiretroviral management are unresolved. The increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.

Anti-HIV Agents↗
PubMed1998

Calmodulin antagonists inhibit apoptosis of CD4+ T-cells from patients with AIDS.

Recent studies indicate that Fas and Fas ligand are involved in apoptosis of T-cells in HIV-infected patients. We have demonstrated that calcium/calmodulin is involved in Fas-mediated apoptosis in human T-cell lines transfected with HIV recombinant cDNA. In the present study, we examined spontaneous apoptosis of T-cells in vitro in peripheral blood obtained from 11 patients with AIDS and 8 HIV-seronegative normal donors and the effect of the calmodulin antagonists, trifluoperazine (TFP) or tamoxifen (TMX), on apoptosis. The results show that: (1) levels of spontaneous apoptosis were higher in PBMCs obtained from patients with AIDS than HIV-negative normal controls and the levels of apoptosis correlated with the severity of disease. (2) The accelerated apoptosis occurred predominantly in CD4+ cells in patients with AIDS. (3) Calmodulin antagonists inhibited the spontaneous apoptosis of CD4+ T-cells from patients with AIDS, which resulted in an increase in the ratio of CD4+ to CD8+ T-cells. (4) The inhibitory effect of calmodulin antagonists on apoptosis was more significant in patients with advanced disease (CDC category C) compared to less severe disease (CDC category B). These results indicate that calmodulin antagonists inhibit HIV-associated apoptosis of CD4+ T-cells, and imply that the calcium/calmodulin play important roles in mediating apoptosis of CD4+ T-cells induced by HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry.

T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.

Adult↗
PubMed1998

Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy.

Data from 1330 human immunodeficiency virus type 1 (HIV-1)-infected patients enrolled in seven antiretroviral treatment trials were analyzed to characterize the clinical benefit of treatment-mediated reductions in plasma HIV-1 RNA levels. The risk of a new AIDS-defining event or death was reduced proportionally to the magnitude of the reduction of the HIV-1 RNA level during the first 6 months of therapy. Pretherapy HIV-1 RNA levels were prognostic independently of on-therapy levels. In addition, the reduction in risk associated with any given reduction of the level of HIV-1 RNA did not vary by pretherapy level. Having either a reduction in HIV-1 RNA level or an increase in CD4+ lymphocyte count, or both, was associated with a delay in clinical disease progression. This indicates that patient prognosis should be assessed using both HIV-1 RNA and CD4+ lymphocyte responses to therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data.

A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (> or = 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (> or = 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the meta-analysis supports the importance of pathogenetic interactions between herpesviruses and HIV.

Acyclovir↗
PubMed1997

Effects of tapering doses of oral prednisone on viral load among HIV-infected patients with unexplained weight loss.

In an exploratory study of virologic and immunomodulatory effects of corticosteroid therapy for wasting syndrome, four HIV-infected adults with recent unexplained weight loss were given tapering doses of prednisone over a 2-month period. Serum neopterin and TNF receptor II levels decreased from baseline after 7 days. An antiretroviral effect was observed initially, peaking on days 14-21 (mean change in HIV-1 branched chain DNA assay on day 21 of -0.52 log10; mean change, from baseline to nadir for each individual, of -0.63 log10); subsequent bDNA levels returned toward baseline as prednisone was tapered. No patient lost weight and there was a mean weight gain of 3.5 kg. Anecdotal reports of corticosteroid benefits in the wasting syndrome may result in part from decreased T cell activation leading to decreased HIV replication, an effect that may be self-limited or that may occur only at higher prednisone doses. Studies involving more targeted immunomodulatory agents for wasting syndrome are warranted.

Adult↗