We describe a human immunodeficiency virus-seronegative man who presented with a skin disorder that we diagnosed as acute generalized exanthematous pustulosis, which we believe was an adverse reaction to combination prophylactic therapy with zidovudine, lamivudine, and protease inhibitor for human immunodeficiency virus. Cutaneous adverse effects are rarely reported with the use of these antiviral drugs.
In order to identify cellular genes differentially expressed during human immunodeficiency virus 1 (HIV-1) infection, we conducted a screen using differential display. The sequence of one of the clones, 0085, was identical to a sequence present in the RNA splicing factor SC35. Since splicing is an essential point of control during HIV gene expression, we carried out additional experiments to examine SC35 expression during HIV infection. RNA blots confirmed that SC35 RNA was induced following HIV infection; a 2-3-fold increase in expression of SC35 RNA was detected by day 2 of HIV infection. Fluorescence-activated cell-sorting revealed concomitant increases in SC35 protein and double staining studies demonstrated that increases in SC35 protein occurred specifically in the HIV-infected cells. Laser scanning confocal microscopy revealed SC35 was associated with 2 microm 'nuclear speckles' in both infected and uninfected cells, suggesting that increases in SC35 accumulated in these nuclear structures and that HIV infection did not alter the intracellular distribution of SC35. These findings indicate that an essential splicing factor is induced after HIV infection, suggesting that the consequences of HIV infection include alterations in relative levels of a splicing factor.
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Health benefits and survival of an exclusively breast-fed infant is dependent on the mother's health; thus, the need for antiretroviral (ARV) intervention for prevention of mother-to-child transmission (PMTCT). Achieving maternal health benefits from these regimens requires adherence to the treatments and close monitoring. We evaluated virologic, immunologic responses, and adherence among women receiving maternal triple ARV prophylaxis consisting of lamivudine/zidovudine and nevirapine or nelfinavir in the Kisumu Breastfeeding Study.
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By intent-to-treat (non-completer = failure) analysis, 10/16 (63%) lopinavir/ritonavir + saquinavir-treated and 7/14 (50%) lopinavir/ritonavir + zidovudine/lamivudine-treated subjects achieved plasma HIV-1 RNA <50 copies/mL (P=0.713) at week 48. Safety, tolerability, metabolic changes and truncal fat increases were similar between groups. Small decreases in the lower extremity fat in the zidovudine/lamivudine group (-6%) and a statistically significant increase in the lower extremity fat in the saquinavir group (+19%) were observed. Lopinavir/ritonavir co-administered with saquinavir 600 or 800 mg twice daily produced saquinavir concentrations similar to those previously reported for saquinavir/ritonavir 1000/100 mg twice daily.
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Mutant viruses were not detected before week 12 with the exception of one subject. At the latest time point on abacavir monotherapy (range, weeks 6-48), 21 out of 43 subjects harboured virus with resistance conferring mutations including single, double and triple combinations of K65R, L74V, Y115F and M184V. The most common mutational pattern was L74V + M184V (11/21 cases). Twenty of the 21 subjects with isolates containing abacavir-associated mutations reached week 48, and upon addition of lamivudine/zidovudiine, 16 out of 20 (80%) had week 48 plasma HIV-1 -RNA below 400 copies/ml. At week 48, 16 out of 46 genotypes were obtained; one of these was wild-type; 15 contained M184V either alone, in combination with K65R and/or L74V and/or Y115F or with thymidine analogue-associated mutations. Week 48 viral load levels for these 15 subjects was low (median 3.43 log10 copies/ml or -1.99 log10 copies reduction from baseline). Genotype correlated well with phenotypic resistance to ABC; four samples with three abacavir-associated mutations had high level abacavir resistance (> 8-fold) and six samples with two or three mutations showed intermediate (4-8-fold) resistance. All samples with single mutations retained full ABC susceptibility.
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Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment.
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1,6-Dihydro-3(2H)-thioxo-6-spiro-(9'-fluorene)-1,2,4-triazin -5(4H)-one (1) has been used to synthesize several analogous compounds via nucleophilic substitution reactions. Spectroscopic data are given in support of the proposed structures. Some of the new products possessed good anti HIV and anticancer activities.
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A controversial subject raised at the Third Conference on Retroviruses and Opportunistic Infections was the relationship between a pregnant woman's viral load and transmission of the virus to her baby. Data presented from one study showed that no mother with a viral load under 25,000 copies/ml transmitted HIV to the infant. A viral load of over 50,000 during delivery was the best predictor of transmission. Other studies detected a weak correlation between viral load and transmission. In mothers receiving AZT during pregnancy, HIV transmission occurred at all detectable viral load levels. Intrapartum versus in utero transmission issues are also addressed.
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This study has determined the effect of liposomal encapsulation on the hematopoietic toxicity and antiviral activity of 3'-azido-3'-deoxythymidine (AZT) in mice. Daily intravenous administration in the dose range 0.4 to 10 mg/kg body weight for 5 days significantly depressed bone marrow cellularity with a corresponding decrease in red blood cell, blood neutrophil, and monocyte numbers. Maximum toxicity was seen at 2 mg/kg or greater. Liposomal encapsulation of AZT and administration at 2 mg/kg abrogated the toxicity of AZT. The neutrophil inflammatory response to thioglycollate injected intraperitoneally was significantly inhibited by AZT at all doses, whereas liposomal AZT was without effect. The inhibitory activity of AZT against Concanavalin A (Con A)-stimulated splenic lymphocyte proliferation in vitro was reduced on liposomal encapsulation of AZT, while treatment of mice with liposomal AZT but not free AZT resulted in a significant reduction of Con A-stimulated proliferation. Liposomal AZT was more effective than AZT in preventing the development of plasma reverse transcriptase activity and the depletion of Thy 1.2(+)-L3T4+ T cells after infection of mice with LP-BM5 retrovirus. These results indicate that AZT-induced hematopoietic toxicity may not be a limiting factor for antiviral therapy, and that the use of liposomes to deliver AZT results in enhanced antiretroviral activity in mice.
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To describe the extent of adherence to the recommended neonatal zidovudine (ZDV) regimen administered to infants who have been exposed to the human immunodeficiency virus (HIV) to prevent mother-to-child transmission of HIV and to determine which maternal factors are associated with compliance.
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Pectin and alginate nanoparticles were prepared by applying a salting out and controlled gelification approach, respectively. The nanoparticles were characterized by attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS) and were further evaluated for zidovudine (AZT) entrapment efficiency. Multipolymeric scaffolds were prepared by crosslinking carboxymethyl cellulose, polyethylene oxide and epsilon caprolactone for entrapment of zidovudine-loaded alginate nanoparticles to impart enhanced controlled release of zidovudine over the time period. Swelling and textural analysis were conducted on the scaffolds. Prepared scaffolds were treated with hydrochloric acid (HCl) to reduce the swelling of matrix in the hydrated environment thereby further controlling the drug release. Drug release studies in phosphate buffered saline (pH 7.4, 37°C) were undertaken on both zidovudine-loaded nanoparticles and native scaffolds containing alginate nanoparticles.
Multiple nucleoside resistance involves specific mutational patterns of the HIV-1 pol gene that are independent of the classic mutations conferring resistance to individual dideoxynucleosides. These include a cluster of five mutations in the reverse-transcriptase (RT) coding region (A62V, V75I, F77L, F116Y, and Q151M) generally referred to as multidrug resistance (MDR) mutations, and insertions of one or several amino acid residues between codons 67 and 70 of RT, a flexible region joining two antiparrallel beta sheets (beta3-beta4 insertions). The objectives of this study were (i) to determine the prevalence of multidrug resistance genotypes (MDR mutations and beta3-beta4 insertions) in a cohort of 632 patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral therapy, and (ii) to analyze the association of multidrug resistance genotypes with other resistance mutations in the RT and protease genes. Among viruses sequenced from these patients, 15 (2.4%) of them contained an insertion and 2 (0.3%) contained a deletion in the beta3-beta4 finger subdomain of RT. In 9 cases, the insertion was associated with a D67S, G, or E mutation. In addition, we identified 13 (2.1%) viruses harboring specific MDR mutations (mainly Q151M and/or A62V, V75I, F116Y). Interestingly, the A62V mutation was found in 6 of the 15 strains with an insertion, whereas the other MDR mutations were not observed in insertion mutant strains. Especially high levels of resistance to zidovudine were observed for viruses with a beta3-beta4 insertion in the background of A62V, L210W, and T215Y. Otherwise, MDR mutations and beta3-beta4 insertions were found in association with the classic mutations conferring resistance to zidovudine, lamivudine, nonnucleoside RT inhibitors, and protease inhibitors, according to treatment history. Finally, we observed a genome with a deletion of codon 70 associated with a Q151M MDR mutation. These data suggest that the emergence of HIV-1 multidrug resistance, which may occur in various genetic contexts, poses a challenging problem in formulating treatment strategies.
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In South Africa, a pregnant woman infected with HIV took zidovudine to protect her fetus, but the child later developed HIV because the woman was not told about breast milk transmission. Women in developing countries have been hit hard by the AIDS epidemic because social inequalities that make it impossible for them to negotiate for safer sex or even to choose their sexual partners. In most developing countries, the only treatment women have access to is the zidovudine that is available only during their participation in clinical trials on prenatal transmission. Activists have expressed concern over programs that attempt to save the lives of babies with no regard for their mothers or other women. Women with HIV need access to health care, to information, and to counselors who can help them make choices. Women must be able to assess whether to risk breast feeding or attempt costly bottle feeding, which may lead to higher levels of infant mortality from bacteria in contaminated water. Women must also be educated so that they can protect their sexual health. In some settings, the topics of sex and sexuality still must be introduced into public discourse. Strong prevention programs are reducing HIV-infection rates among young women in parts of Tanzania, among pregnant women and prostitutes in Dakar, among prostitutes in Thailand and Nepal, and among street children in Brazil. Effective programs must consider AIDS a social issue and address education, equality, and information access.
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In long-term follow-up studies, irregular longitudinal data are observed when individuals are assessed repeatedly over time but at uncommon and irregularly spaced time points. Modeling the covariance structure for this type of data is challenging, as it requires specification of a covariance function that is positive definite. Moreover, in certain settings, careful modeling of the covariance structure for irregular longitudinal data can be crucial in order to ensure no bias arises in the mean structure. Two common settings where this occurs are studies with 'outcome-dependent follow-up' and studies with 'ignorable missing data'. 'Outcome-dependent follow-up' occurs when individuals with a history of poor health outcomes had more follow-up measurements, and the intervals between the repeated measurements were shorter. When the follow-up time process only depends on previous outcomes, likelihood-based methods can still provide consistent estimates of the regression parameters, given that both the mean and covariance structures of the irregular longitudinal data are correctly specified and no model for the follow-up time process is required. For 'ignorable missing data', the missing data mechanism does not need to be specified, but valid likelihood-based inference requires correct specification of the covariance structure. In both cases, flexible modeling approaches for the covariance structure are essential. In this paper, we develop a flexible approach to modeling the covariance structure for irregular continuous longitudinal data using the partial autocorrelation function and the variance function. In particular, we propose semiparametric non-stationary partial autocorrelation function models, which do not suffer from complex positive definiteness restrictions like the autocorrelation function. We describe a Bayesian approach, discuss computational issues, and apply the proposed methods to CD4 count data from a pediatric AIDS clinical trial.
Background. Existing data on anthropomorphic changes in resource-limited settings primarily come from observational or cross-sectional studies. Data from randomized clinical trials are needed to inform treatment decisions in these areas of the world. Methods. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized evaluation of the efficacy of emtricitabine/tenofovir + efavirenz (FTC/TDF + EFV) vs lamivudine/zidovudine + efavirenz (3TC/ZDV + EFV) for the initial treatment of human immunodeficiency virus (HIV)-1-infected individuals from resource-diverse settings. Changes in anthropomorphic measures were analyzed using mixed-effect models for repeated measurements, using all available measurements at weeks 48, 96, and 144. Intent-to-treat results are presented; as-treated results were similar. Results. Five hundred twenty-six participants were randomized to FTC/TDF + EFV, and 519 participants were randomized to 3TC/ZDV + EFV. Significantly greater increases from baseline to week 144 were seen among those randomized to FTC/TDF + EFV vs 3TC/ZDV + EFV in all measures except waist-to-hip ratio, with the following mean changes: weight, 4.8 vs 3.0 kg; body mass index, 1.8 vs 1.1 kg/m(2); mid-arm, 1.7 vs 0.7 cm; waist, 5.2 vs 4.3 cm; hip, 3.8 vs 1.4 cm; and mid-thigh circumference, 3.1 vs 0.9 cm. There were 7 clinical diagnoses of lipoatrophy in the 3TC/ZDV + EFV arm compared with none in the FTC/TDF + EFV arm. The proportion of overweight or obese participants increased from 25% (week 0) to 42% (week 144) for FTC/TDF + EFV and from 26% to 38% for 3TC/ZDV + EFV. Conclusions. Our findings support first-line use of FTC/TDF + EFV in resource-limited settings and emphasize the need for interventions to limit weight gain among overweight or obese HIV-infected participants in all settings.
We collected reports of BBF exposures among HCWs occurring from January 2001 to December 2003 at a 2000-bed tertiary care medical center in northern Taiwan. HCWs were requested to report BBF exposures immediately after each exposure, which required completing a report sheet of questions concerning the exposure. The HCW was also required to visit an infectious diseases specialist who would decide on the appropriate management in each case.
A group of 116 antiretroviral naive patients, with CD4 cell counts 100-500 x 10(6) cells/l, were randomized to: AZT 200 mg three times daily plus ddC 0.75 mg three times daily versus AZT 100 mg three times daily plus ddC 0.375 mg three times daily and followed-up regularly for 48 weeks.
To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48.
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Renal metabolism by UDP-glucuronosyltransferase (UGT) enzymes is central to the clearance of many drugs. However, significant discrepancies about the relative abundance and activity of individual UGT enzymes in the normal kidney prevail among reports, whereas glucuronidation in tumoral kidney has not been examined. In this study, we performed an extensive profiling of glucuronidation metabolism in normal (n = 12) and tumor (n = 14) kidneys using targeted mass spectrometry quantification of human UGTs. We then correlated UGT protein concentrations with mRNA levels assessed by quantitative polymerase chain reaction and with conjugation activity for the major renal UGTs. Beyond the wide interindividual variability in expression levels observed among kidney samples, UGT1A9, UGT2B7, and UGT1A6 are the most abundant renal UGTs in both normal and tumoral tissues based on protein quantification. In normal kidney tissues, only UGT1A9 protein levels correlated with mRNA levels, whereas UGT1A6, UGT1A9, and UGT2B7 quantification correlated significantly with their mRNA levels in tumor kidneys. Data support that posttranscriptional regulation of UGT2B7 and UGT1A6 expression is modulating glucuronidation in the kidney. Importantly, our study reveals a significant decreased glucuronidation capacity of neoplastic kidneys versus normal kidneys that is paralleled by drastically reduced UGT1A9 and UGT2B7 mRNA and protein expression. UGT2B7 activity is the most repressed in tumors relative to normal tissues, with a 96-fold decrease in zidovudine metabolism, whereas propofol and sorafenib glucuronidation is decreased by 7.6- and 5.2-fold, respectively. Findings demonstrate that renal drug metabolism is predominantly mediated by UGT1A9 and UGT2B7 and is greatly reduced in kidney tumors.
Many children with human immunodeficiency virus-1 (HIV-1) have chronic problems with growth and nutrition, yet limited information is available to identify infected children at high risk for growth abnormalities. Using data from the prospective, multicenter P2C2 HIV study, we evaluated the relationships between maternal and infant clinical and laboratory factors and impaired growth in this cohort.
Four clinical research units.
A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.
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Nucleoside reverse transcriptase inhibitors (NRTIs) are used in the treatment of human immunodeficiency virus (HIV). Since the analogue 5-fluorouracil increases Candida albicans virulence in vitro, and zidovudine therapy is associated with enhanced C. albicans adherence and biofilm formation, we investigated the effects of commonly used NRTIs on the virulence of C. albicans isolated from 21 antiretroviral-naïve HIV/AIDS patients. The isolates were exposed to didanosine, lamivudine, stavudine and zidovudine at their expected patient serum peak levels and at one-half and two times these levels for 24h and 72 h. Assays assessing changes in adherence, proliferation, biofilm formation and antifungal susceptibility were performed. No differences in these virulence characteristics of isolates exposed to NRTIs were noted in most cases. However, at 24h and 72 h a significant increase in the rate of proliferation was observed in response to two-fold the peak concentration of lamivudine. The results suggest a limited effect of NRTIs on C. albicans virulence.
to study trends in mortality and survival in patients with AIDS attending an ID unit.
We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir-ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005.
These models were used to derive clinical cutoffs (CCOs) for 6 nucleoside/nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, abacavir, and tenofovir), 3 unboosted protease inhibitors (PIs; indinavir, amprenavir, and nelfinavir), and 4 ritonavir-boosted PIs (indinavir/ritonavir, amprenavir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir). The CCOs were defined as the phenotypic resistance levels (fold change [FC]) associated with a 20% and 80% loss of predicted wild-type drug effect and depended on the drug-specific dynamic range of the assay.
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The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.
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A multicenter case-control study of children with HIV at 26 institutions participating in the Pediatric Oncology Group. Forty-three case patients with a new malignancy and 74 control patients without a malignancy were matched based on the duration of their infection. Patients were enrolled between January 1992 and July 1998.