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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highlights from the 38th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) included a tribute to Jonathan Mann and Mary-Lou Clements Mann and a review of HIV drugs recently approved and currently in development. Information is provided about efavirenz, abacavir, amprenavir, and adefovir, including the classification, dosing, and side effects of these drugs. Data from recent trials of these new drugs can be used to determine the best course of treatment for treatment-naive and treatment-experienced patients. New nucleoside reverse transcriptase inhibitors reviewed are lodenosine (FDDA), FTC, BCH-10652, and DAPD. Non-nucleoside reverse transcriptase inhibitors described include MKC 442 and PNU 142721. Other drugs under development include bis(POC) PMPA, a nucleotide RTI, and several protease inhibitors. T-20, an enzyme that interferes with envelope fusion, is also in development.
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PMID:Antiretroviral update from the Interscience Conference on Antimicrobial Agents and Chemotherapy. 1136 83

Several sessions at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) presented results of trials of anti-HIV drugs. ABT-378/r, a combination of the protease inhibitor ABT-378 with ritonavir, shows great promise. T-20 (pentafuside) shows significant benefits in treating advanced HIV disease. Tenofovir DF (PMPA) appears to have benefits in treating people who are taking four or fewer other drugs. Efavirenz (Sustiva) in combination with AZT and 3TC continues to show effectiveness at 72 weeks. Once-daily dosing regimens are also under development, which should make adherence to treatment programs easier for patients.
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PMID:Anti-HIV therapy trials: new studies and follow-up of existing trials. 1136 57

Simple affordable interventions are needed to reduce vertical human immunodeficiency virus (HIV) transmission in developing countries. The efficacy of 2 low doses (4 mg/kg, subcutaneously) or 1 high dose (30 mg/kg, subcutaneously) of the reverse-transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) to protect newborn macaques against simian immunodeficiency virus (SIV) infection was investigated. Thirteen newborn macaques were inoculated orally with virulent SIVmac251. The 4 placebo-treated animals (group A) became persistently infected. Groups B and C (n=4 in each group) received 2 4-mg/kg doses of PMPA, either 4 h before and 20 h after (group B) or 1 and 25 h after SIV inoculation (group C). One animal (group D) received a single 30-mg/kg dose of PMPA 1 h after SIV inoculation. Despite evidence of an initial transient infection, 3 group B animals, 2 group C animals, and the group D animal were SIV negative and seronegative at ages 19-23 months. Immune activation with recall antigens or pharmacologic immunosuppression with corticosteroids failed to reactivate viral replication. These data suggest that 1 or 2 doses of PMPA may protect human newborns against intrapartum HIV infection.
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PMID:Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. 1147 Nov

New antiretroviral drugs with activity against strains of human immunodeficiency virus type 1 (HIV-1) with non-B subtypes and with resistance to current antiretroviral drugs are needed. The activity of two nucleotide analogs, tenofovir and adefovir (PMPA and PMEA, respectively), against non-B subtypes and nucleoside-resistant primary HIV-1 isolates was assessed. Tenofovir and adefovir were fully active against a panel of subtypes A, C, D, E, F, G, and group O primary HIV-1 isolates as compared with their respective activity against subtype B isolates. Moreover, the susceptibility of a panel of 10 primary HIV-1 isolates with >10-fold mean resistance to zidovudine, lamivudine, and abacavir was within 2.2-fold of wild-type tenofovir susceptibility for each isolate. An oral prodrug of tenofovir, tenofovir disoproxil fumarate (DF), is currently in phase III clinical trials for the treatment of HIV-1 infection. These in vitro susceptibility results suggest that tenofovir DF may be active in vivo against HIV-1 with nucleoside resistance as well as against HIV-1 with non-B subtypes.
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PMID:Tenofovir, adefovir, and zidovudine susceptibilities of primary human immunodeficiency virus type 1 isolates with non-B subtypes or nucleoside resistance. 1152 86

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.
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PMID:Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. 1155 62

Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.
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PMID:New developments in anti-HIV chemotherapy. 1156 82

The presence of the lamivudine-associated M184V RT mutation increases tenofovir susceptibility in multiple HIV genotypes. Tenofovir is uniquely active against multinucleoside-resistant HIV expressing the Q151M mutation, but shows reduced susceptibility to the T69S insertion mutations. HIV with common forms of zidovudine and lamivudine resistance are susceptible to tenofovir, corroborating phase II clinical results demonstrating the activity of tenofovir DF in treatment-experienced patients.
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PMID:Antiviral activity of tenofovir (PMPA) against nucleoside-resistant clinical HIV samples. 1156 51

PMPA, an acyclic nucleoside phosphonate analog, is a potent inhibitor of HIV. In the cells, PMPA is efficiently phosphorylated by intracellular kinases to produce PMPApp, the pharmacologically active metabolite. Despite its demonstrated antiviral potency, PMPA has limited cell permeability presumably resulting from the presence of two negative charges on the phosphonyl group. To enhance intracellular concentrations of PMPA, we developed a prodrug, selectively metabolized inside cells. GS-7340 (9-[(R)-2-[[[[(S)-1-(isopropoxycarbonyl)ethyl] amino] phenoxy-phosphinyl]-methoxy] propyl] adenine) is a prodrug which is orally bioavailable in dogs as the intact prodrug and has demonstrated anti-HIV activity in cell culture of over 1000-fold greater than that of PMPA. The metabolism of PMPA in peripheral blood mononuclear cells (PBMC), red blood cells (RBC) and plasma was examined following exposure of whole blood to PMPA or GS-7340 at concentrations similar to ones observed systemically following oral administration in dogs. Following 1 hour incubation with whole blood, GS-7340 was stable in plasma, produced high levels of PMPA and its phosphorylated metabolites in PBMC but not in RBC. No intact prodrug was present in PBMC. The only other species present in PBMC was monoalaninyl PMPA. The levels of PMPA and the phosphorylated metabolites were over 20 times greater than those after incubation with PMPA. The dog and human blood data were similar. The intracellular levels of PMPA and PMPApp were roughly proportional to GS-7340 over a 10-fold concentration range indicating a lack of saturability of uptake and phosphorylation. Since PMPApp is the species responsible for antiviral activity of PMPA, the high intracellular levels of PMPApp should be an important indicator of greater clinical efficacy of GS-7340.
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PMID:Metabolism of GS-7340, a novel phenyl monophosphoramidate intracellular prodrug of PMPA, in blood. 1156 63

The diastereomers of GS-7171, aryl phosphoramidate derivatives of the anti-HIV nucleotide analog 9-[2-R-(phosphonomethoxy)propyl]adenine (tenofovir, PMPA), were isolated by batch elution chromatography and continuous simulated moving bed chromatography. The absolute configuration of the more pharmacologically active diastereomer, GS-7340, was determined to be (R,S,S) by single crystal x-ray crystallography.
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PMID:Purification of PMPA amidate prodrugs by SMB chromatography and x-ray crystallography of the diastereomerically pure GS-7340. 1156 62

An antisense oligodeoxynucleotide against the human immunodeficiency virus type 1 (HIV-1) Rev response element, a ribozyme complementary to the HIV-1 5'-LTR, and the reverse transcriptase inhibitors 9-(2-phosphonylmethoxyethyl) adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)-adenine (PMPA) inhibited virus replication in monocyte-derived macrophages more effectively when delivered in pH-sensitive liposomes compared to the free drugs.
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PMID:Enhanced inhibition of HIV-1 replication in macrophages by antisense oligonucleotides, ribozymes and acyclic nucleoside phosphonate analogs delivered in pH-sensitive liposomes. 1156 68


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