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We examined 388 individuals (75.5% male, mean age 45.38years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10years (RV10) was 12.15% (95%CI: 10.99-13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39-6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18-4.14).
After 12 months of follow-up, plasma viral load was reduced similarly in both groups, with 78% (NFV) and 83% (NVP) of patients achieving a VL <200 copies/ml. A significant increase in CD4 T cells was observed in both groups (mean: +182 cells, P=0.001). Both regimens were similarly effective in reducing activated T cells (CD38 and DR). A significant increase of both CD4 and CD8 CD28 T cells occurred in both arms of treatment. Patients of both regimens showed a significant decrease of activated memory (CD45RA-CD45RO+) CD8 T cells and a clear increase of naive (CD45RA+CD45RO-) CD8 T cells. Peripheral blood mononuclear cell proliferative responses to polyclonal stimuli (CD3 and CD3 +CD28) as well as to ubiquitous cytomegalovirus antigen increased significantly in both groups after 12 months of follow-up. Nevertheless, neither at baseline nor after 1 year of treatment, these patients showed any significant T-cell responsiveness to HIV-1 recombinant proteins gp160 or p24.
The switch strategy of substituting ZDV for d4T-based HAART led to satisfactory overall clinical outcomes. However, it resulted in a relatively high incidence of mild to severe anemia and increased burden for the program and the patients.
The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.
ADR data associated with the use of HAART from November 2005 to December 2007 was collected retrospectively from records of patients using the ART treatment from NACO at a tertiary referral centre under the National Pharmacovigilance Programme. These ADRs were analyzed for causality (WHO scale), severity (Hartwig et al. scale) and preventability (Schumock and Thornton scale).
Zidovudine (ZDV) has been the cornerstone of antiretroviral (ARV) therapy for pregnant women infected with HIV-1 in the prevention of mother-to-child transmission (MTCT) and remains the only licensed ARV for use in pregnancy. We explored the current and future roles of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT of HIV-1.
Observational cohort study.
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Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2', 3'-didehydro-2', 3'-deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3' azido-3'-deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs.
In this cohort, treatment before the onset of AIDS was not universal. Less than 10% of children were treated with Zidovudine or intravenous gamma globulin before 6 months of age, with a steady increase to about 40% after 3 years of life. An estimated 23% (95% confidence interval: 15% to 31%) of infected children develop AIDS before the age of 1 year, and nearly 40% (27% to 50%) by 4 years. Ten percent (5% to 16%) die before age 1 year and 28% (16% to 41%) before age 5 years. Twenty-four months after the AIDS diagnosis, an estimated 48% (36% to 70%) of the children are still alive. Although after the age of 1 year immunologic abnormalities became increasingly common, the proportion of infected children with significant HIV-related symptoms or signs declined.
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An open, case-controlled, pharmacokinetic and 24-week continuous treatment pilot study.
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In ART naïve Ugandan children, HOMA-IR changed significantly after 48 weeks of ART and correlated with monocyte activation.
Deletions in the beta 3-beta 4 hairpin loop of human immunodeficiency virus type 1 reverse transcriptase (RT) are associated with the emergence of multidrug resistance. Common mutational patterns involve the deletion of Asp67 (Delta 67) and mutations such as K70R and T215F or T215Y, or the deletion of Thr69 (Delta 69) and mutations of the Q151M complex. Human immunodeficiency virus type 1 clones containing Delta 69 in a multidrug-resistant sequence background, including the Q151M complex and substitutions K103N, Y181C, M184V, and G190A, showed high-level resistance to all tested nucleoside RT inhibitors. In a multidrug-resistant sequence context, the deletion increases viral replication capacity. By itself, Delta 69 conferred increased susceptibility to beta-d-(+)-3'-azido-3'-deoxythymidine (AZT) and beta-l-(-)-2',3'-dideoxy-3'-thiacytidine resistance. Here, we use transient kinetics to show that, in a wild-type sequence background, Delta 69 does not affect the discrimination between AZT triphosphate and 2'-deoxythymidine 5'-triphosphate, but decreases the catalytic efficiency of the incorporation of beta-l-(-)-2',3'-dideoxy-3'-thiacytidine triphosphate relative to 2'-deoxycytidine 5'-triphosphate. In comparison with the wild-type RT, the Delta 69 mutant showed decreased ability to excise primers terminated with AZT monophosphate in the presence of ATP or pyrophosphate (PPi). These data support the role of the excision mechanism in mediating AZT hypersusceptibility. In addition, we demonstrate that the deletion has no effect on resistance to foscarnet (a PPi analogue) on phenotypic and nucleotide incorporation assays carried out with viral clones and recombinant enzymes, respectively. The results of molecular modeling studies suggest that the side chains of Lys65, Asp67, and Lys219 could play an important role in AZT hypersusceptibility mediated by Delta 69, whereas in the absence of Thr69, local structural rearrangements affecting the beta 3-beta 4 and beta 11a-beta 12 loops of the 66-kDa subunit of the RT could reduce the accessibility of the PPi donor to the terminating nucleotide at the 3' end of the primer.
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All HIV-infected pregnant women identified after the release of the ACTG 076 results who were offered zidovudine therapy to reduce maternal-infant transmission.
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The AST results showed a significant (p ≤ 0.05) decreased in the zidovudine plus anti-TB plus neutrosec treated group (125.50 ± 22.71) compared with zidovudine plus anti-TB treated group (399. 10 ± 0.45). It further showed non-significant decreased (p ≥ 0.05) in the ALP levels between the zidovudine plus anti TB treated group (317.10 ± 73.48) and the zidovudine plus anti TB plus neutrosec treated group (203.20 ± 35.97). There was a non-significant (p ≤ 0.05) decrease in the MDA level of the zidovudine plus anti-TB plus neutrosec treated group compared with the zidovudine plus anti-TB treated group.
Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old.
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There was no statistically significant difference among the groups with respect to maternal weight gain. There were more pregnancy resorptions in the group receiving high-dose zidovudine (150 mg/kg/day) throughout embryogenesis than in the control group (P = 0.001, respectively). Four major structural anomalies were noted among the 689 fetuses examined, but zidovudine was not associated with an increased frequency of congenital anomalies in rats when it was administered in doses similar to, 3-, and 15-fold higher than the regimen recommended for adult humans. The drug, however, was embryocidal in the high-dose group (P = 0.002).
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The AIDS Clinical Trials Group/US Department of Defense p24 antigen-based consensus assay was used to determine in vitro susceptibility of 57 primary clinical isolates and three laboratory strains of HIV-1 to XM323, zidovudine, zalcitabine (ddC), and didanosine (ddI).
Eight HIV-positive mothers delivered nine babies; all the infants received antiretroviral therapy. Three (37.5%) and five mothers (62.5%) were administered single- and multidrug therapy, respectively. Intravenous zidovudine was administered to four infants (50%) at birth. Breastfeeding was discouraged for all the infants. All the infants were negative for HIV, although two were lost to follow-up. Third trimester maternal viral copy numbers were less than 1,000 copies/mL with a median CD4+ count of 325/µL (92-729/µL). Among the nine infants, two were preterm (22.2%) and three had low birth weights (33.3%).
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2650 patients were followed-up for 2456 person-years and reported 114 ADRs (incidence rate = 4.6/100 person-years).There were more females 1706(64%) and 73(64%) of the ADRs were reported by women. Overall, 61(54%) of ADRs were reported by patients on AZT with 54(47%) of these occurring in patients on AZT/NVP. The commonest ADRs reported were pain 25(30%) and skinrash 10(18%). Most ADRs were grade 1(39%) with only 1% being life threatening (grade 4). Adjusted GEE analysis showed that ADR was less likely to occur in patients on longer duration of ART compared to the first six months on treatment; 6-12 months AOR 0.38(95% CI:0.16-0.91) and 12-24 months AOR 0.34(95% CI:0.16-0.73) respectively. Compared to patients on TDF, ADR was less likely to occur in patients on d4T and AZT AOR 0.18(95% CI 0.05-0.64) and AOR 0.24(95% CI:0.7-0.9) respectively. Age, gender and CD4 count were not significantly associated with ADRs.
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Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the two drugs. Rifabutin is more lipid soluble than is rifampin, resulting in more-extensive tissue uptake, a larger volume of distribution, lower maximum plasma concentrations, lower trough concentrations, a longer terminal half-life, and higher tissue-to-plasma drug concentration ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. Rifabutin does not affect the pharmacokinetics of antiretroviral drugs that are excreted in the urine. Although rifabutin decreases plasma concentrations of zidovudine, this finding does not appear to be clinically relevant. When administered during rifabutin prophylaxis, fluconazole decreases the incidence of Mycobacterium avium complex bacteremia. The coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin and decreased plasma concentrations of clarithromycin; however, the plasma concentration of clarithromycin's active metabolite is increased.
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Differences in HRQoL between study groups at 1 year follow-up were not detected. Nevertheless, a trend toward improvement was observed in summary health scores in ZDV/3TC/NVP-treated patients.
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Separations of five diastereoisomers of nucleoside phosphoramidate derivatives (pronucleotides) were performed by both HPLC method using derivatized cellulose and amylose chiral stationary phases and CE method using anionic cyclodextrins added in the background electrolyte (BGE). An optimal baseline separation (Rs > 1.5) was readily obtained with all silica-based celluloses and amyloses using in a normal-phase methodology. Capillary electrophoresis was used as an alternative technique to HPLC for the separation of pronucleotides. The diastereoisomers were fully resolved with sulfated cyclodextrins at both BGE pH (2.5 and 6.2). Limits of detection and limits of quantification, calculated for both methods, are up to 200 times higher in CE separations than in HPLC separations. The analytical HPLC method was then applied in a preliminary study for the pronucleotide 1 quantification in cellular extract.
Comparison of the amino acid sequence of the RT and protease genes in successive samples showed the rapid reappearance of wild-type viral variants in 12 of the 14 patients studied. Wild-type virus replaced the mutant strains 14 days to 2 months after the interruption of therapy, even in patients with a long treatment history.
Factors associated with higher odds of treatment failure were severe depression [OR 3.7; p-value 0.002; 95% CI 1.6-8.5] and discontinuing ART [OR 4.4; p-value 0.02; 95% CI 1.3-14.7]. Factors associated with lower odds of treatment failure were age = 42 [OR 0.3; p-value 0.007; 95% CI 0.1-0.7], taking ART on time [OR 0.2; p-value 0.02; 95% CI 0.05-0.8], time on ART > 4 years [OR 0.6; p-value 0.02; 95% CI 0.3-0.9] and female sex [OR 0.4; p-value 0.02; 95% CI 0.2-0.8]. There was statistically significant difference between CD4 count and viral load results in diagnosing treatment failure [OR 8.7; p-value 0.0005; 95% CI 3.6-21.2].
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From January 1992 through May 1993, 31 patients with adenocarcinoma of the pancreas or hepatocellular carcinoma were treated with weekly oral methotrexate (7.5 mg/M2 every 6 hours for 6 doses) and continuous oral AZT (200 mg four times daily). Patients were treated for a total of 6 months or until disease progression. The median age was 66 (range 44-79) and the median KPS was 80. No patient had received prior chemotherapy. Hematologic toxicity was severe with 50% of patients developing hemoglobins less than 8 gm/dl and 70% with granulocyte counts less than 1000 per mm3. One patient achieved a radiographic complete remission and 2 had stable disease. Two-thirds of patients progressed within 2 months of beginning therapy. The combination of methotrexate and AZT is an inactive regimen in pancreatic and hepatocellular carcinoma and is associated with considerable toxicity.
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Women who were prospectively enrolled in a natural history study of HIV-1 infection in women and infants. Sixteen HIV-1-infected women whose infants became infected were matched by CD4+ cell percentage and use of zidovudine during pregnancy with women whose infants did not become infected.
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To evaluate the incidence of cancers in uninfected children born to HIV-infected mothers.