35 research outputs found
A Randomized, Controlled Trial of Indinavir, Zidovudine, and Lamivudine in Adults with Advanced Human Immunodeficiency Virus Type 1 Infection and Prior Antiretroviral Therapy
A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection, ⩽50 CD4 cells/mm3, and extensive prior zidovudine therapy. Patients received indinavir, 800 mg every 8 h; zidovudine, 200 mg every 8 h, and lamivudine, 150 mg twice daily; or all 3 drugs for 24 weeks. In an intention-to-treat analysis, proportions of patients with HIV-1 RNA <500 and <50 copies/mL, respectively, at week 24 were 56% and 45% in the indinavir-zido-vudine-lamivudine group, 3% and 2% in the indinavir group, and 0% in the zidovudinelamivudine group. Observed mean CD4 cell increases were 95, 78, and 6 cells/mm3 in the three-, one-, and two-drug arms, respectively. Regimens were generally well tolerated. Patients with advanced HIV-1 infection benefit from triple therapy with indinavir, zidovudine, and lamivudine, although the proportion with optimal response appeared to be lower in patients with low CD4 cell count
Primary Lung Dendritic Cell Cultures to Assess Efficacy of Spectinamide-1599 Against Intracellular Mycobacterium tuberculosis
There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, because IFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence of IFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination with IFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide
Residual Human Immunodeficiency Virus (HIV) Type 1 RNA and DNA in Lymph Nodes and HIV RNA in Genital Secretions and in Cerebrospinal Fluid after Suppression of Viremia for 2 Years
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for ⩽2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartment
Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy
Background: The new protease inhibitors are potent
inhibitors of the human immunodeficiency virus
(HIV), and in combination with other antiretroviral
drugs they may be able to cause profound and sustained
suppression of HIV replication.
Methods: In this double-blind study, 97 HIV-infected
patients who had received zidovudine treatment
for at least 6 months and had 50 to 400 CD4 cells per
cubic millimeter and at least 20,000 copies of HIV
RNA per milliliter were randomly assigned to one of
three treatments for up to 52 weeks: 800 mg of indinavir
every eight hours; 200 mg of zidovudine every
eight hours combined with 150 mg of lamivudine
twice daily; or all three drugs. The patients were followed
to monitor the occurrence of adverse events
and changes in viral load and CD4 cell counts.
Results: The decrease in HIV RNA over the first 24
weeks was greater in the three-drug group than in
the other groups (P�0.001 for each comparison).
RNA levels decreased to less than 500 copies per
milliliter at week 24 in 28 of 31 patients in the threedrug
group (90 percent), 12 of 28 patients in the indinavir
group (43 percent), and none of 30 patients
in the zidovudine–lamivudine group. The increase in
CD4 cell counts over the first 24 weeks was greater
in the two groups receiving indinavir than in the zidovudine–
lamivudine group (P<0.01 for each comparison).
The changes in the viral load and the CD4
cell count persisted for up to 52 weeks. All the regimens
were generally well tolerated.
Conclusions: In most HIV-infected patients with
prior antiretroviral therapy, the combination of indinavir,
zidovudine, and lamivudine reduces levels of
HIV RNA to less than 500 copies per milliliter for as
long as one year. (N Engl J Med 1997;337:734-9.
Residual Human Immunodeficiency Virus (HIV) Type 1 RNA and DNA in Lymph Nodes and HIV RNA in Genital Secretions and in Cerebrospinal Fluid after Suppression of Viremia for 2 Years
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for ⩽2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartment
Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection
Background: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1)
integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs.
Methods: We conducted two identical trials in different geographic regions to evaluate the
safety and efficacy of raltegravir, as compared with placebo, in combination with
optimized background therapy, in patients infected with HIV-1 that has triple-class
drug resistance in whom antiretroviral therapy had failed. Patients were randomly
assigned to raltegravir or placebo in a 2:1 ratio.
Results: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir
and placebo groups, respectively) received the study drug. Seventeen of the 699
patients (2.4%) discontinued the study before week 16. Discontinuation was related
to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients
(1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies
were consistent. At week 16, counting noncompletion as treatment failure, 355 of
458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter,
as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of
HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in
61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients,
and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons).
Without adjustment for the length of follow-up, cancers were detected
in 3.5% of
raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of
drug-related adverse events were similar in the raltegravir and placebo groups.
Conclusions: In HIV-infected patients with limited treatment options, raltegravir plus optimized
background therapy provided better viral suppression than optimized background
therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and
NCT00293254.
Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection
Background: We evaluated the efficacy of raltegravir and the development of viral resistance in
two identical trials involving patients who were infected with human immunodeficiency
virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral
therapy had failed.
Methods: We conducted subgroup analyses of the data from week 48 in both studies according
to baseline prognostic factors. Genotyping of the integrase gene was performed
in raltegravir recipients who had virologic failure.
Results: Virologic responses to raltegravir were consistently superior to responses to placebo,
regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic
or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in
optimized background therapy; or demographic characteristics. Among patients in the
two studies combined who were using both enfuvirtide and darunavir for the first
time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of
raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50
copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and
in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for
the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%)
had virologic failure. Genotyping was performed in 94 raltegravir recipients with
virologic failure. Integrase mutations known to be associated with phenotypic resistance
to raltegravir arose during treatment in 64 patients (68%). Forty-eight of
these 64 patients (75%) had two or more resistance-associated mutations.
Conclusions: When combined with an optimized background regimen in both studies, a consistently
favorable treatment effect of raltegravir over placebo was shown in clinically
relevant subgroups of patients, including those with baseline characteristics that typically
predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low
CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov
numbers, NCT00293267 and NCT00293254.
Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Common Problem Drugs and How to Prescribe Them.
In vitro and in vivo evaluation of synergism between anti-tubercular spectinamides and non-classical tuberculosis antibiotics
Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored