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- Tenofovir disoproxil fumarate-associated nephrotoxicity in HIV-infected patients: a prospective controlled study. [Journal Article, Research Support, Non-U.S. Gov't]
- J Med Assoc Thai 2013 Apr; 96(4):432-9.
To evaluate all renal functions in patients receiving TDF and other nucleoside analogues.A prospective controlled study evaluating glomerular and tubular functions was conducted in patients receiving either TDF- or AZT-containing antiretroviral therapy regimen between 2008 and 2009 at King Chulalongkorn Memorial Hospital, Bangkok, ThailandOf 51 patients, there were 39 and 12 patients, with the mean age of 40.03 +/- 7.7 and 37.2 +/- 7.6 years in the TDF and AZT groups. There was no diference between the two groups, except longer HIV infection duration, higher patient number with previous antiretroviral therapy and undetectable HIV RNA, and higher CD4 count in the TDF group. All and most patients had received lamivudine and a non-nucleoside analogue. The mean change of eGFR from the baseline to the six months of follow-up was +/-1.32 and +/- 5.88 mL/minute in the TDF and AZT groups. Proximal tubular dysfunction was not noted at three and six months of follow-up. However patients in the TDF group had lower serum phosphate and higher renal potassium loss than the AZT group at six months of follow-up (p = 0.08 and p = 0.09, respectively). No patients in the two groups with distal tubular dysfunctions were notedTo our knowledge, this is the first prospective controlled study extensively evaluating all renal functions in patients receiving TDF andAZT There are no differences in the eGFR decline between the two groups during the six months of follow-up. However, a trend towards greater renal loss of potassium and phosphate is noted in the TDF group. A study with longer duration of follow-up is needed
- Comparison of tenofovir, Zidovudine, or Stavudine as part of first-line antiretroviral therapy in a resource-limited-setting: a cohort study. [Journal Article]
- PLoS One 2013; 8(5):e64459.
Tenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT).In a prospective cohort study we included ART naïve patients aged ≥17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling.Of 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively.In routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent.
- Interferon-alpha (IFN-alpha) suppresses HTLV-1 gene expression and cell cycling, while IFN-alpha combined with zidovudin induces p53 signaling and apoptosis in HTLV-1-infected cells. [JOURNAL ARTICLE]
- Retrovirology 2013 May 20; 10(1):52.
BACKGROUND:Human T-cell leukemia virus type-1 (HTLV-1) is the causative retrovirus of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 gene expression is maintained at low levels in vivo by unknown mechanisms. A combination therapy of interferon-alpha (IFN-alpha) and zidovudin (AZT) shows therapeutic effects in ATL patients, although its mechanism is also obscure. We previously found that viral gene expression in IL-2-dependent HTLV-1-infected T-cells (ILTs) derived from ATL patients was markedly suppressed by stromal cells through a type I IFN response. Here, we investigated the effects of IFN-alpha with or without AZT on viral gene expression and cell growth in ILTs.
RESULTS:ILTs expressed variable but lower amounts of HTLV-1 Tax protein than HTLV-1-transformed HUT102 cells. Following the addition of IFN-alpha, the amounts of HTLV-1 p19 in the supernatants of these cells decreased in three days, while HTLV-1 gene expression decreased only in ILTs but not HUT102 cells. IFN-alpha also suppressed the spontaneous HTLV-1 induction in primary ATL cells cultured for 24 h. A time course study using ILTs revealed that the levels of intracellular Tax proteins decreased in the first 24 h after addition of IFN-alpha, before the reduction in HTLV-1 mRNA levels. The initial decreases of Tax protein following IFN-alpha treatment were observed in 6 of 7 ILT lines tested, although the reduction rates varied among ILT lines. An RNA-dependent protein kinase (PKR)-inhibitor reversed IFN-mediated suppression of Tax in ILTs. IFN-alpha also induced cell cycle arrest at the G0/G1 phase and suppressed NF-kappaB activities in these cells. AZT alone did not affect HTLV-1 gene expression, cell viability or NF-kappaB activities. AZT combined with IFN-alpha markedly induced cell apoptosis associated with phosphorylation of p53 and induction of p53-responsive genes in ILTs.
CONCLUSIONS:IFN-alpha suppressed HTLV-1 gene expression at least through a PKR-mediated mechanism, and also induced cell cycle arrest in ILTs. In combination with AZT, IFN-alpha further induced p53 signaling and cell apoptosis in these cells. These findings suggest that HTLV-1-infected cells at an IL-2-dependent stage retain susceptibility to type I IFN-mediated regulation of viral expression, and partly explain how AZT/IFN-alpha produces therapeutic effects in ATL.
- Role of DNA Repair Pathways in Response to Zidovudine-induced DNA Damage in Immortalized Human Liver THLE2 Cells. [Journal Article]
- Int J Biomed Sci 2013 Mar; 9(1):18-25.
The nucleoside reverse transcriptase inhibitor zidovudine (3'-azido-3'-dexoythymidine, AZT) can be incorporated into DNA and cause DNA damage. Previously, we determined that the human hepatocellular carcinoma HepG2 cells are more susceptible to AZT-induced toxicities than the immortalized normal human liver THLE2 cells and the nucleotide excision repair (NER) pathway plays an essential role in the response to AZT-induced DNA damage. We have now investigated if the effects of AZT treatment on the expression levels of genes related to DNA damage and repair pathways contribute to the differences in sensitivity to AZT treatment between HepG2 cells and THLE2 cells. Of total 84 genes related to DNA damage and repair, two, five, and six genes were up-regulated more than 1.5-fold at 50, 500, and 2,500 µM AZT groups compared with that of control THLE2 cells. Seven genes showed a decreased expression of more than 1.5-fold following the 2,500 µM AZT treatment. Two-sided multivariate analysis of variance indicated that the change in expression of genes involved in apoptosis, cell cycle, and DNA repair pathways was significant only at 2,500 µM AZT. Statistically significant dose-related increases were identified in XPC gene expression and GTF2H1 protein level after the AZT treatments, which implicated the NER pathway in response to the DNA damage induced by AZT. In contrast, AZT treatment did not alter significantly the expression of the APE1 gene or the levels of APE1 protein. These results indicate that the NER repair pathway is involved in AZT-induced DNA damage response in immortalized human hepatic THLE2 cells.
- Characterization of antiviral activity of a benzamide derivative AH0109 against HIV-1 infection. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2013 May 13.
In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug-resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an EC50 value of 0.7μM in HIV-1 susceptible CD4+ C8166 T cells. Mechanistic analysis revealed that AH0109 significantly inhibits both HIV-1 reverse transcription and viral cDNA nuclear import. Furthermore, our infection experiments indicated that AH0109 is capable of disrupting the replication of HIV-1 strains that are resistant to the routinely used anti-HIV-1 drugs AZT, 3TC, nevirapine and reltagravir. Together, these findings provide evidence for a newly identified antiviral molecule that can potentially be developed as an anti-HIV-1 agent.
- AZT impairs immunological recovery on first-line ART: collaborative analysis of cohort studies in Southern Africa. [JOURNAL ARTICLE]
- AIDS 2013 May 8.
OBJECTIVES:: Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa.
DESIGN:: Cohort study.
METHODS::Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year.
RESULTS::72 597 patients starting ART, including 19 758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were -16 cells/μl (95% CI -18 to -14) at 1 year and -56 cells/μl (95% CI -59 to -52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22-1.61).
CONCLUSIONS::In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART.
- Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest. [JOURNAL ARTICLE]
- Ann Hematol 2013 May 5.
To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO-induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis.
- Harnessing autophagy for cell fate control gene therapy. [JOURNAL ARTICLE]
- Autophagy 2013 Apr 17; 9(7)
We hypothesized that rapamycin, through induction of autophagy and promotion of an antiapoptotic phenotype, would permit lentiviral (LV)-based transgene delivery to human T-Rapa cells, which are being tested in phase II clinical trials in the setting of allogeneic hematopoietic cell transplantation. Manufactured T-Rapa cells were exposed to supernatant enriched for a LV vector encoding a fusion protein consisting of truncated CD19 (for cell surface marking) and DTYMK/TMPKΔ, which provides "cell-fate control" due to its ability to phosphorylate (activate) AZT prodrug. LV-transduction in rapamycin-treated T-Rapa cells: (1) resulted in mitochondrial autophagy and a resultant antiapoptotic phenotype, which was reversed by the autophagy inhibitor 3-MA; (2) yielded changes in MAP1LC3B and SQSTM1 expression, which were reversed by 3-MA; and (3) increased T-Rapa cell expression of the CD19-DTYMKΔ fusion protein, despite their reduced proliferative status. Importantly, although the transgene-expressing T-Rapa cells expressed an antiapoptotic phenotype, they were highly susceptible to cell death via AZT exposure both in vitro and in vivo (in a human-into-mouse xenogeneic transplantation model). Therefore, rapamycin induction of T cell autophagy can be used for gene therapy applications, including the CD19-DTYMKΔ cell-fate control axis to improve the safety of T cell immuno-gene therapy.
- Azidothymidine (AZT) leads to arterial stiffening and intima-media thickening in mice. [Journal Article]
- J Biomech 2013 May 31; 46(9):1540-7.
HIV positive patients on highly active antiretroviral therapy (HAART) have shown elevated incidence of a number of non-AIDS defining co-morbidities, including cardiovascular disease. Given that HAART regimens contain a combination of at least three drugs, that disease management often requires adjustment of these regimens, and HIV, independent of HAART, also plays a role in development of co-morbidities, determining the role of specific HAART drugs and HIV infection itself from clinical data remains challenging. To characterize specific mediators and underlying mechanisms of disease, in vitro and in vivo animal models are required, in parallel with clinical data. Given its low cost azidothymidine (AZT) contributes to the backbone of a large proportion of HAART treated patients in the developing world where much of the global burden of HIV resides. The goal of this study was to test the hypothesis that AZT can lead to proatherogenic changes including the subclinical markers of arterial stiffening and intima-media thickening in mice. AZT (100mg/kg) or vehicle was administered to wild-type FVB/N mice via oral gavage for 35 days. Cylindrical biaxial biomechanical tests on the common carotid arteries and suprarenal aortas exhibited arterial stiffening in AZT mice compared to controls. Multiphoton microscopy and histology demonstrated that AZT led to increased intima-media thickness. These data correlated with decreased elastin content and increased protease activity as measured by cathepsin zymography; no differences were observed in collagen content or organization, in vivo axial stretch, or opening angle. Thus, this study suggests the drug AZT has significant effects on the development of subclinical markers of atherosclerosis.
- Human rElafin Inhibits HIV-1 Replication in Its Natural Target Cells. [Journal Article]
- Biores Open Access 2013 Apr; 2(2):128-37.
Trappin-2/elafin is a novel innate immune factor that belongs to the serine protease inhibitor family and has known antibacterial, antifungal, and antiviral properties. In this study, we further investigated the anti-HIV activity of elafin using different cellular models and both X4- and R5-HIV-1 laboratory strains. We compared the antiviral activity of human recombinant elafin (rElafin) with three well-known antiretroviral drugs, AZT, tenofovir, and enfuvirtide. We have found that when the virus is pre-incubated with rElafin prior to the infection of the cells, HIV-1 replication is significantly inhibited. In target T cells and human peripheral blood mononuclear cells, maximal inhibition was achieved using submicromolar concentrations, and rElafin was found to be as potent as enfuvirtide, showing its potential for therapeutic application. We also show data on the mechanism of the antiviral activity of rElafin. We have demonstrated that rElafin neither binds to CD4, CXCR4, or CCR5 host cell receptors, nor to the viral glycoproteins gp120 and gp41. Furthermore, in our cell-to-cell fusion assays, in contrast to enfuvirtide, rElafin failed to block cell fusion. Altogether our results indicate that rElafin interferes with HIV replication at the early steps of its cycle but with a different mechanism of action than enfuvirtide. This study provides the first experimental evidence that elafin inhibits HIV replication in its natural target cells; therefore, elafin might have potential for its development as a new anti-HIV drug or microbicide.