A prospective cohort study involving HIV-1 seropositive pregnant mothers and their infants.
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Our purpose was to determine the prevalence of mutations of resistance to nucleoside inhibitors of reverse transcriptase (NIRT) and protease inhibitors (PI) in the HIV-1 genotype of naïve infected subjects in the prisons of the Autonomous Community of Valencia, Spain.
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A total of 144 patients (70%) reported chemosensory complaints, 91 (44%) reported both taste and smell complaints, 47 (23%) reported only taste complaints, and six (3%) reported only smell complaints. Many patients complained that drugs interfered with their sense of taste, or that medications tasted bad. Higher chemosensory complaint scores were associated with a greater number of medications taken, tobacco use, and hay fever. Patients with chemosensory complaints had significantly lower scores in all domains of the MOS-HIV than those without complaints. Quality of life as measured by the MOS-HIV was lower in patients with chemosensory complaints even after controlling for number of AIDS diagnoses, number of medications, CD4 cell count, and HIV-1 viral load.
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The preliminary results of the Concorde trial demonstrated the transient clinical benefit of monotherapy with zidovudine (AZT) in asymptomatic persons infected with human immunodeficiency virus type 1 (HIV-1). This result, which has been widely disseminated and discussed, was predictable given the previous demonstration of the development of resistance to AZT in isolates from individuals receiving prolonged treatment with the drug and given the finding that didanosine (ddI) is more efficacious than continued therapy with AZT in individuals who have received > or = 6 months of AZT monotherapy. On the basis of these findings, interest in combinations of antiretroviral agents has continued to grow. Many in vitro studies of nucleoside and nonnucleoside inhibitors of reverse transcriptase combined with interferon-alpha or inhibitors of protease have been published. In addition, numerous clinical trials of various combinations have been completed or are under way. Dr. Martin Hirsch and his colleagues at the Massachusetts General Hospital have been among the leaders of this effort. He and Dr. Angela Caliendo review, in this AIDS Commentary, the current state of our knowledge regarding the potential utility of combination therapy for infection with HIV-1.
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This article describes a very simple route for synthesizing novel lipophilic phosphate bis(t-bu-SATE) prodrugs of acyclic cyclobutylated C-nucleosides such as isocytosine 12 and 9-deazaadenine 19, which were prepared from 1,1-gem cyclobutyl dicarboxylate. Synthesized compounds were evaluated as potential antiviral agents against HIV virus. Some phosphate SATE prodrugs were more active against HIV than parent nucleosides.
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The value of k for HIV-1 RNA in plasma was positively and significantly associated with the mean plasma nevirapine concentration during the first 2 weeks of therapy (P = 0.011) and the baseline HIV-1 RNA (P = 0.008). Patients with a higher exposure to nevirapine reached undetectable levels of HIV-1 RNA in plasma more rapidly (P = 0.03). From 12 weeks on, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (P < 0.02).
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[(3)H]Hypoxanthine was detected in TR-MUL5 cells and TR-MUL5 cell-cultured medium 3 hours after [(3)H]adenosine incubation, indicating that the hypoxanthine is produced in TR-MUL5 cells. [(3)H]Adenosine was taken up into TR-MUL5 cells, which express mRNAs of nucleoside transporters (ENT1-2 and CNT1-2), in an Na(+)-independent and concentration-dependent manner (Km = 20 μM). Moreover, 100 μM nitrobenzylmercaptopurine riboside (NBMPR) and azidothymidine, which are inhibitors of ENT2, inhibited [(3)H]adenosine uptake, suggesting that ENT2 is a major contributor to adenosine transport in Müller cells. [(3)H]Hypoxanthine was eliminated from the rat vitreous humor and this process was inhibited in the presence of NBMPR. [(3)H]Hypoxanthine uptake by TR-iBRB2 cells took place in an Na(+)-independent and concentration-dependent manner with Km values of 4.3 μM and 2.9 mM, and was inhibited by 100 μM NBMPR.
3'-Azido-3'-deoxythymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) was obtained by growing HTLV-IIIB in C8166 cell cultures in the presence of inhibitory concentrations of AZT. The AZT-resistant HIV-1 was capable of replicating, as measured by infectious virus yield, and inducing cytopathic effect in the presence of AZT concentrations able to completely suppress the replication of parental HTLV-IIIB. Cloning of the AZT-resistant HIV-1 revealed that a number of different variants of HIV-1 with various degrees of sensitivity to AZT emerged during propagation of HTLV-IIIB in C8166 cells in the presence of the drug. PCR experiments performed on DNA extracted from C8166 cells infected with a resistant strain revealed that viral DNA was produced in the presence of inhibitory concentrations of AZT, while viral DNA in C8166 cells infected with the parental virus was drastically inhibited. Reverse transcriptase isolated from the AZT-resistant HIV-1 variant failed to show resistance to AZT 5'-triphosphate.
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Prevention of HIV transmission after accidental occupational exposure is possible. Combination therapy is more effective than monotherapy in treating HIV infections. Zidovudine (AZT or ZDV) is effective in postexposure prophylaxis; the combination of zidovudine and lamivudine (3TC) and indinavir (IDV) has greater antiretroviral activity than zidovudine alone does. The requirements for effective HIV postexposure prophylaxis may be somewhat different than those for optimum HIV treatment in the chronically ill HIV-positive patient. Ophthalmologists should have an in-depth knowledge of current thinking regarding HIV pathophysiology and treatment.
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HIV-1-infected patients had more hypodiploid cells (19%), fewer G0-G1 phase cells (70%) and more S phase cells (10%) than did healthy controls (8%, 85% and 5% respectively; P = 0.002). Patients with sustained suppression of plasma HIV-1 RNA levels after antiretroviral therapy had only modest improvements in these indices. In contrast, patients who failed to suppress plasma HIV-1 RNA levels had decreases in G0-G1 cells to 54% (P = 0.032) and increases in S phase cells to 24% (P = 0.055). Plasma HIV-1 RNA levels and the percentage of S phase cells were correlated (r, 0.23; P = 0.047). In patients failing antiretroviral therapy, there was an inverse correlation between the percentage of G0-G1 cells and expression of the activation antigens CD38 and HLA-DR on CD4 cells (r, -0.409; P = 0.016) and CD8 cells (r, -0.363; P = 0.035).
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We examined the effect of HIV infection on src-family protein tyrosine kinase (PTK) activity to determine if alterations in src-family PTK activity could contribute to the HIV-related chronic immune system activation observed in patients infected with HIV.
The CSF influx rate of zidovudine was the highest, although moderate, followed by that of stavudine. The permeability coefficients of the other drugs tested were low. Zidovudine influx into the CSF is independent of thymidine transport systems, and more importantly is limited by an efflux mechanism. This efflux involves an apical (CSF-facing) carrier belonging to the solute carrier (Slc) 22 family of organic anion transporters, and can be inhibited by a therapeutic concentration of benzbromarone.
Chronic hepatitis C virus infection is currently one of the leading causes of morbidity and mortality in HIV-infected individuals, mainly in hemophiliacs and intravenous drug users. The bidirectional interferences between hepatitis C virus and HIV have clinical consequences and complicate the management of coinfected individuals.
A substudy was performed among 19 participants of a randomized 48-week trial, comparing continuing first-line zidovudine/lamivudine (ZDV/3TC) with switching to TDF/emtricitabine (FTC). GFR was measured with [(125)I]-iothalamate (mGFR) and effective renal plasma flow (ERPF) with [(131)I]-hippuran. eGFR and tubular effects were assessed using plasma and urine samples.
In this small prospective study of HIV-infected children, mutations in the reverse transcriptase coding region, syncytium-inducing viral phenotype, higher HIV-1 RNA load and lower CD4+ cell count were significantly correlated with increased risk of HIV clinical disease progression.
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Calanolide is a naturally occurring non-nucleoside reverse transcriptase inhibitor synthesized from a rain forest tree. It is reported to be highly effective in a test tube against wild type HIV and Zidovudine-resistant HIV. A dose-ranging study is enrolling at the University of Texas Medical Branch. Contact information is provided.
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Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6-18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.
The binding of novel nucleoside derivatives (2-7) to the Human Serum Albumin (HSA) was studied using zidovudine (AZT), as standard compound. The applicability of two different techniques to separate unbound drug from drug-protein complex was analyzed: the gel filtration and ultrafiltration methods. Ultrafiltration was found to be an adequate procedure for the separation of unbounded drug from the drug-protein complex. Incubation temperature ranging from 0 to 37 degrees C did not modify considerably the bound fractions. The same effects were observed as HSA concentration was modified. Binding assays of studied compounds to purified 1% (w/v) HSA at 0 degrees C, indicate that bound fraction of 2-7 ranges from 13 to 47%, exhibiting a higher affinity to HSA than AZT (12%), which would introduce some interesting improvements in their pharmacokinetic properties. In addition, by means of displacement studies using HSA site specific drugs such as diazepam and salicylate, it was determined that AZT binds to site I of the HSA molecule, by a mainly entropy driven process (DeltaS = 10.834 cal/mol degrees K), being these observations extensive to 2-7. Some structural basis to explain enhanced affinity of these novel derivatives was also established.
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In comparing two treatments under a typical sequential clinical trial setting, a 50-50 randomization design generates reliable data for making efficient inferences about the treatment difference for the benefit of patients in the general population. However, if the treatment difference is large and the endpoint of the study is potentially fatal, it does not seem appropriate to sacrifice a large number of study patients who are assigned to the inferior arm. An adaptive design is a data-dependent treatment allocation rule that sequentially uses accumulating information about the treatment difference during the trial to modify the allocation rule for new study patients. In this article, we utilize real trials from AIDS and cancer to illustrate the advantage of using adaptive designs. Specifically we show that, with adaptive designs, the loss of power for testing the equality of two treatments is negligible. Moreover, the study patients do not have to pay a handsome price for the benefit of future patients. We also propose multi-stage adaptive rules to relax the administrative burden of implementing the study and to handle continuous response variables, such as the failure time in survival analysis.
In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.
Retrospective (before 1985) and prospective (after 1985) follow-up of a group of French haemophiliacs.
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In 565 adult cases of AIDS at autopsy, Pneumocystis carinii pneumonia (PCP) remained the most common cause of death, but both the frequency of and number of deaths of PCP declined over time. Deaths from bacterial sepsis, cytomegalovirus infection, Mycobacterium avium complex infection, and toxoplasmosis also declined during this period, but mortality from fungal infections, tuberculosis, encephalopathy, and causes unrelated to AIDS increased. The death rate from malignant lymphoma remained high. Kaposi's sarcoma (KS) continued to occur more frequently in patients whose risk factor for human immunodeficiency virus infection (HIV) was homosexuality or bisexuality, but the death rate from KS was greatest for patients with a risk factor of blood exposure to HIV. Survival was shorter and deaths from tuberculosis more common in patients with a history of intravenous drug use. Overall survival of patients in other AIDS risk groups increased over time, particularly in those treated with antiretroviral therapy. The organ system distribution of major opportunistic infections and neoplasms was similar throughout the years of the study. The lung was the most frequent organ involved by AIDS-associated diseases leading to death, followed by the gastrointestinal tract and the central nervous system.
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Perinatal HIV transmission has declined significantly in New York State (NYS) since implementation of a 3-part regimen of zidovudine prophylaxis in the antenatal, intrapartum, and newborn periods. This study describes the factors associated with perinatal transmission in NYS from 1997 to 2000, the first 4 years of NYS's comprehensive program in which all HIV-exposed newborns were identified through universal HIV testing of newborns.
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It is known that infected macrophages play an important role in HIV pathogenesis acting as a reservoir for dissemination of the virus to various organs. Enhanced and/or specific delivery of anti-HIV agents to infected cells is expected to improve their therapeutic index by increasing efficacy and reducing toxicity. Acetylated low density lipoproteins (AcLDL) are known to be taken up by macrophages via scavenger receptors and appear to be good carriers for targeting drug molecules to macrophages. This study investigated the delivery of 3'-azido-3'-deoxythymidine (AZT), an anti-HIV agent, to macrophages using AcLDL. Since the incorporation of AZT into AcLDL was found to be low, several derivatives of AZT including 5'-O-13-oxamyristate-AZT (5'-O-oxaMyr-AZT) have been synthesized as prodrugs. The prodrugs were incorporated into AcLDL using two different methods, namely the contact method and the microemulsion method. Our results demonstrated that the microemulsion method was more effective. The physicochemical properties of the AcLDL/prodrug complex were evaluated by electrophoresis and electron microscopy (EM). Incubation of the complex with plasma resulted in little distribution of the incorporated drug molecules from AcLDL to other components of the plasma, suggesting that the complex was quite stable. Cellular uptake studies using J774.A and U937 demonstrated that AcLDL/prodrug was taken up about 10 times more than AZT. The presence of excess AcLDL was found to inhibit the cellular uptake of AcLDL/5'-O-oxaMyr-AZT by macrophages while excess high density lipoprotein (HDL) or low density lipoprotein (LDL) was found to have little effect, suggesting that the AcLDL/prodrug complex is taken up into macrophages via the scavenger receptor.
In 1999, for the first time in South Africa, a Mother-to-Child HIV Transmission (MTCT) prevention programme was implemented at the routine primary care level and not as part of a research protocol. A total of 264 women attending prenatal care in these clinics were interviewed in Xhosa using a standardized questionnaire. All had been offered HIV testing, and 95% had accepted. Women who had not been tested were four times more likely to believe that in the community families reject HIV-positive women (p<0.005). Of women who tested, 19% were HIV positive and 83% had told their partner that they had taken the test. HIV-positive women who had not disclosed testing to their partners were three times more likely to believe that, in the community, partners are violent towards HIV-positive women (p<0.005); 86% stated that they would have taken AZT if found to be HIV positive. Only 11% considered that the use of formula feeding indicated that a woman was HIV positive. In conclusion, routine prenatal HIV testing and interventions to reduce perinatal HIV transmission are acceptable to the majority of women in a South African urban township, despite an awareness of discrimination in the community towards HIV-positive women.
A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance.
To determine whether proton magnetic resonance spectroscopy (MRS) demonstrates central nervous system abnormalities in asymptomatic HIV-1-infected individuals.
Se analizaron los datos de 3535 mujeres embarazadas seropositivas incluidas en el Estudio Colaborativo Europeo Ucraniano entre 2008 y 2010. Se investigaron los factores asociados a la recepción de una monoterapia con zidovudina —y no el tratamiento antirretroviral combinado prenatal— y las tasas de transmisión de madre a hijo del VIH.