Abstracts of all trials identified were examined independently by two authors. We identified 15,922 references and examined 81 in detail. Data were abstracted independently using a standardized form.
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The simian immunodeficiency virus (SIV)-newborn rhesus macaque model of AIDS can be used to study directly the virulence of viral mutants which are resistant to antiviral drugs. A viral mutant called SIVmac79A6.1, isolated from an SIV-infected macaque after prolonged zidovudine treatment, was found to have a double-base-pair change at codon 151 of reverse transcriptase, resulting in a glutamine to methionine substitution (Q151M). This mutation was associated with more than 100-fold increased resistance to zidovudine and low-level cross-resistance to other dideoxynucleoside analogs. To determine whether this Q151M mutation affects viral virulence, four newborn macaques were inoculated intravenously with a biological clone of this drug-resistant SIVmac79A6.1 mutant; two of these animals were also treated orally with zidovudine. All four animals showed persistent viremia, and two of the four animals developed fatal immunodeficiency at 3 and 8 months of age, respectively. The remaining two animals had CD4+ T-cell depletion and clinical symptoms of AIDS at 22 months. No phenotypic or genotypic reversion of virus to the wild type could be detected in any of the four animals. These results demonstrate that the Q151M mutation in SIV reverse transcriptase does not reduce viral virulence.
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The prognostic role of platelet (PLT) counts was evaluated in a cohort of 1,533 HIV-1-infected subjects followed for a median of 21 months. Thrombocytopenia (TCP), defined as a PLT count < or = 100 x 10(9)/L was present at enrollment in 11.2% of cases, with counts < or = 50 x 10(9)/L (severe TCP) in 5.3%. With the subjects with normal PLT counts (PLT >150 x 10(9)/L) as the reference group, the relative risk of developing acquired immunodeficiency syndrome (AIDS) was 0.8 [95% confidence interval (CI) 0.5-1.3, p = 0.4] for subjects with severe TCP, 2.1 (95% CI 1.4-3.1, p = 0.002) for those with PLT counts ranging from 51 to 100 x 10(9)/L (moderate TCP), and 1.6 (95% CI 1.2-2.1, p = 0.0004) for those with borderline PLT values (PLT ranging from 101 to 150 x 10(9)/L). Most of the risk increase associated with moderate TCP and borderline PLT values was explained by a higher prevalence of subjects with an older age and lower CD4+ cell counts. However, at multivariable analysis considering age, sex, risk group, and zidovudine (ZDV) treatment, the risk for subjects with severe TCP remained significantly lower than that for subjects with moderate TCP and borderline values. These results suggest the existence of different types of HIV-1-associated TCP and also suggest that severe TCP (which often arises in the early phases of infection) is not related to disease progression.
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To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART).
A sensitive LC/MS/MS assay for determining zidovudine (ZDV) and lamivudine (3TC) in human plasma was validated to support antiretroviral pharmacology research programs. After addition of stable labeled isotopic zidovudine (ZDV-IS) and lamivudine (3TC-IS) as internal standard, a solid-phase extraction was performed with an Oasis HLB 1 cm(3) cartridge, with recoveries of 92.3% for ZDV and 93.9% for 3TC. A Phenomonex Synergi Hydro-RP (2.0 ×150 mm) reversed-phase analytical column was utilized for chromatographic separation. The mobile phase consisted of an aqueous solution of 15% acetonitrile and 0.1% acetic acid. Detection was accomplished by ESI/MS/MS in the positive ion mode, monitoring 268/127, 271/130, 230/112 and 233/115 transitions, for ZDV, ZDV-IS, 3TC and 3TC-IS, respectively. The method was linear from 1 to 3000 ng/mL with a minimum quantifiable limit of 1 ng/mL when 100 μL of plasma was analyzed. Validation results demonstrated high accuracy (≤8.3% deviation) and high precision (≤10% CV) for the quality control samples. The method was also shown to be specific and reproducible. The value of the high sensitivity was demonstrated by quantitation of approximately 100 existing samples that had ZDV below the limit of quantitation using a previously validated, less sensitive HPLC-UV method utilized in the laboratory.
The methods of synthesis of conjugates of anti-HIV nucleosides with various compounds, such as protease inhibitors, peptides, polysaccharides, and bicyclames, are considered; they are designated for the combined therapy of HIV.
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New York City women (321) enrolled during 1986-1993 in an observational cohort study were analyzed retrospectively to determine the effectiveness of antenatal zidovudine in reducing perinatal transmission of human immunodeficiency virus type 1 (HIV-1) in women with various CD4+ lymphocyte counts (< 200, 200-499, > 499/microL). When CD4+ lymphocyte level was controlled for, women prescribed zidovudine during pregnancy were less likely to transmit HIV-1 to their infants (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.92). There was no conclusive evidence that efficacy of zidovudine depended on CD4+ lymphocyte level, suggesting that women with severe CD4+ cell depression, who are at highest risk of transmitting HIV-1, may also benefit from zidovudine. Antenatal zidovudine treatment alone may substantially lower the risk of perinatal HIV-1 transmission. These data are consistent with the results of AIDS Clinical Trial Group protocol 076 and suggest that a substantial portion of zidovudine's protective effect may occur when used during the antenatal period.
Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.
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Utilization rates for antenatal, intrapartum, and neonatal ZDV increased from 41% to 70% during the 4-year period. Use of combination antiretrovirals increased from fewer than 2% of women in 1994 to 1995 to 35% in 1997 to 1998. Antenatal and neonatal ZDV use increased each year, but intrapartum ZDV use reached a plateau after 1996. Mother-infant pairs with the following characteristics were less likely to have received a complete 3-part ZDV regimen: older maternal age, CD4 count >500 cells/microl, preterm birth, cocaine or heroin use during pregnancy, positive newborn drug screen test result, and smoking or alcohol use during pregnancy. By multivariate logistic regression adjusted for hospital and year of birth, cocaine or heroin use during pregnancy (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.3), maternal CD4 count (OR, 0.4; 95% CI, 0.2-0.8; comparing <200 with >500 cells/microl), and preterm birth (OR, 1.6; 95% CI, 1.1-2.5) remained independently associated with not receiving the complete ZDV regimen.
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There are limited numbers of drugs that are available in formulations that are appropriate for neonates and few studies assessing resistance among infants born to human immunodeficiency virus (HIV)-infected women.
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We report here the results of studies examining the ability of zidovudine (AZT) to influence the establishment and maintenance of long-term marrow cultures (LTMC) using marrow from murine immunodeficient mice (MAIDS). Normal C57BL6 mice were infected with LP-BM5 (MuLV) immunodeficiency virus (10 micrograms total protein) intraperitoneally. Five weeks after viral infection, mice were sacrificed and marrow was harvested from normal non-virus-infected and virus-infected animals. LTMC were established in the presence or absence of dose escalation of AZT, that is, 10(-6), 5 x 10(-7), and 10(-7) M in vitro. Compared with controls prepared from normal bone marrow, LTMC using MAIDS-infected marrow failed to establish and subsequently release supernatant-derived mononuclear cells. The addition of AZT was ineffective in either establishing LTMC or consistently producing mononuclear cells. Measurements of erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) precursors were all depressed and none were observed after 5 weeks of culture. Treatment with AZT failed to reverse this depression of stem cell progenitors. Microscopic examination of cultures at 10 weeks demonstrated a failure of MAIDS-LTMC to establish an adequate stromal layer compared to LTMC prepared form non-virus-infected controls. This data indicate that LP-BM5 MuLV infection alters the establishment of a normal functioning hematopoietic microenvironment or stroma. Acknowledging that important differences between MAIDS and human AIDS exist, the implications of these findings concerning the establishment of the immunodeficiency disease state in human immunodeficiency virus infection is discussed.
Membrane-interactive phospholipids (PLs), previously evaluated for activity against HIV-1 in vitro, are known to affect late steps in viral replication. Studies were done to determine the effects of PL analogs on post-translational processing of HIV-1 proteins, binding of viral surface gp160/gp120 to CD4 receptor, and HIV-1-induced cell fusion. Results of this investigation indicated that PL alone (1-octadecanamido-2-ethoxypropyl-rac-3-phosphocholine, CP-51) and PL-AZT conjugate (1-octadecanamido-2-ethoxypropyl-rac-3-phospho-3'- azido-3'-deoxythymidine, CP-92) have no effect on HIV-1-induced syntheses or processing of gp160/gp120, pr51, p24, or p17 (including myristoylation) in infected cells. Progeny HIV-1 particles made in CP-92-treated H9IIIB cells contained gp120, pr51, and p24; however, these virus particles had reduced capacity to bind to CD4+ cells. Both CP-51 and CP-92 inhibited syncytium (cell fusion) formation between treated HIV-1-infected cells and uninfected CD4+ cells, and, they reduced HIV-1 gp160/gp120 binding to CD4+ cells and monoclonal antibody. These results suggest that anti-HIV-1 activity of PL compounds involves alteration of cell surface membranes and viral envelopes. Phospholipid compounds are a novel class of membrane interactive compounds with potential use in blocking the spread of HIV-1 infection and pathogenesis in AIDS.
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Prolonged treatment of AIDS patients with azidothymidine results in the development of resistance to the drug which correlates with the appearance of point mutations in the reverse transcriptase (RT) coding region within the HIV-1 pol gene. Kinetic studies of interactions of wild type RT and its mutants harbouring the above mutations with substrates and azidothymidine 5'-triphosphate (AZTTP) have been carried out. The complete mutant containing all the above described mutations possess the highest resistance on all the templates tested. Significant increases in resistance for mutants 67,70,215 and 67,215 on all the templates have also been observed. Inhibition of mutant enzymes by AZTTP depends on the template used.
In the absence of randomized and prospective clinical studies to guide decision making, this analysis indicates that induction chemotherapy may be a reasonable option for selected HIV-infected patients with AML and adequate immune function.
Combination antiretroviral therapy (cART)-treated adults participating in an international HIV trial with haemoglobin and mean corpuscular volume (MCV) measurements at entry were categorized by presence of anaemia (haemoglobin ≤14 g/dl in men and ≤12 g/dl in women) and, for those with anaemia, by type [microcytic (MCV < 80 fl), normocytic (80-100 fl), macrocytic (>100 fl)]. We analysed the association between inflammation (IL-6 and hsCRP) and coagulation (D-dimer) and haemoglobin, controlling for demographics (age, race and sex), BMI, HIV plasma RNA levels, CD4⁺ T-cell counts (nadir and baseline), Karnofsky score, previous AIDS diagnosis, hepatitis B/C coinfection and use of zidovudine.
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The overall prevalence of anemia was 23.1%. The prevalence of anemia in HAART naïve and HAART experienced persons was 29.9% and 16.2%, respectively (P = 0.014). Presence of opportunistic infections (P = 0.004, 95% CI = 1.69-15.46), CD4 count <200 cells/µl (P = 0.001, 95% CI = 2.57-36.89) and rural residence (P = 0.03, 95% CI = 1.12-10.39) were found to be predictors of anemia for HAART naïve participants. On the other hand, HAART regimen (ZDV/3TC/NVP) (P = 0.019, 95% CI = 0.01-1.24) and the duration of HAART (P = 0.007, 95% CI = 0.003-0.40.24) were found to be predictors of anemia for HAART experienced groups.
Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
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Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated.
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Increasing geometric mean levels of plasma HIV-1 RNA were associated with increasing rates of transmission: the rate was 0 percent among women with less than 1000 copies per milliliter (0 of 57), 16.6 percent among women with 1000 to 10,000 copies per milliliter (32 of 193), 21.3 percent among women with 10,001 to 50,000 copies per milliliter (39 of 183), 30.9 percent among women with 50,001 to 100,000 copies per milliliter (17 of 55), and 40.6 percent among women with more than 100,000 copies per milliliter (26 of 64) (P<0.001). The treatment status of one woman was unknown. The highest rate of transmission was among women whose plasma HIV-1 RNA levels exceeded 100,000 copies per milliliter and who had not received zidovudine (19 of 30 women, 63.3 percent). Neither higher HIV-1 RNA levels early in pregnancy nor higher levels late in pregnancy were associated with the timing of infection in the infants.
To determine the associations between HIV encephalitis and other central nervous system (CNS) pathology, viral burden, cognitive impairment, zidovudine therapy and risk group in AIDS patients.
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To assess the antiviral efficacy, safety, and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression.
Randomised trials comparing any intervention aimed at decreasing the risk of mother-to-child transmission of HIV infection compared with placebo or no treatment, or any two or more interventions aimed at decreasing the risk of mother-to-child transmission of HIV infection.
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Postexposure prophylaxis represents an advance in the management of percutaneous exposure to HIV in the workplace, but its efficacy in other settings needs further study. Three types of occupational exposure, percutaneous, mucous membrane, skin contact or loss of skin integrity, the postexposure prophylaxis to be used or offered, and the risk data and assessment for HIV acquisition are examined. Analysis of HIV transmission through percutaneous exposure reveals that occupational risk for health care workers is increased by deep injury to the exposed worker, visible blood on the injuring device, exposure of the device to source patients' vein or artery, and source patient's death from AIDS within 60 days of the accident. Prophylaxis for percutaneous exposure, if indicated, should be initiated within 1 to 2 hours to be effective. HIV antibody titers should be measured immediately and at 6 weeks, 12 weeks, and 6 months after exposure. AZT prophylaxis following percutaneous occupational exposure has dramatically decreased transmission in this setting and multiple drug regimens have become the standard of care to further increase efficacy. Sexual contact is the most frequent means of transmitting HIV infection and reducing exposure is the mainstay of public health efforts. Prophylaxis after non-occupational exposures such as sexual intercourse or sharing needles could potentially decrease transmission, although efficacy has not yet been demonstrated. Routine prophylaxis after sexual exposure may be an ineffective strategy.
The association between postnatal human immunodeficiency virus type 1 (HIV-1) transmission and maternal highly active antiretroviral therapy (HAART) after infant extended antiretroviral prophylaxis was assessed.
We randomly assigned 400 HIV-infected pregnant women who sought care at two public-sector primary health facilities in Lusaka, Zambia. One was excluded, 200 were assigned to receive a single oral dose of 300 mg tenofovir disoproxil fumarate with 200 mg emtricitabine under direct observation, and 199 to receive no study drug. Short-course zidovudine and intrapartum nevirapine were offered to all HIV-infected women, according to the local standard of care. Women who met national criteria for antiretroviral therapy were referred for care and not enrolled. Our primary study outcome was resistance to non-nucleoside reverse transcriptase inhibitors at 6 weeks after delivery. We used standard population sequencing to determine HIV genotypes. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00204308.