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

We tried to establish whether MT-4 cells that were infected with HIV-1(HTLV-III(B)) at a high multiplicity of infection (m.o.i.=1), and subsequently treated with high concentrations of anti-HIV drugs for several days, would be able to resume virus production after the antivirals are washed away. The HIV inhibitors studied were the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and lamivudine, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and loviride, the acyclic nucleoside phosphonate RT inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (tenofovir) and the protease inhibitors (PIs) saquinavir, indinavir and ritonavir. The compounds, at 50 and 500 times their 50% inhibitory concentration (IC(50), determined at a m.o.i.=0.01), were added immediately after virus adsorption and removed after an incubation period of 0 (wash control), 24, 48 or 72 h. Virus breakthrough was monitored by microscopical examination of cytopathicity, viral infectivity (yield) and p24 levels in the supernatant. The presence of HIV-1(HTLV-III(B)) proviral DNA was determined after a 72-h incubation period. None of the antiviral drugs studied was able to prevent resumption of viral growth after removal of the compound. Tenofovir, lamivudine and the NNRTIs nevirapine, delavirdine and loviride, at 500 times their respective IC(50), were able to delay viral breakthrough for approximately 2-3 days. The NRTI zidovudine and the PIs saquinavir, indinavir and ritonavir, under the same conditions, were not able to delay viral breakthrough at all. Virus recovered upon treatment proved as sensitive to the anti-HIV drugs as wild-type virus. Our results suggest that viral replication at the cellular level was not completely inhibited by drug monotherapy. Consequently, virus rebounded when drug therapy stopped. In conclusion, our findings suggest that drug holidays would result in viral breakthrough, even after virus replication has been previously suppressed by adequate drug levels.
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PMID:In vitro evaluation of the effect of temporary removal of HIV drug pressure. 1086 59

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

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

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

Patients who cannot construct a viable antiretroviral regimen with approved drugs will now have easier access to tenofovir, a drug that is currently experimental but may be approved in about six months. Tenofovir is significant because it appears to maintain its antiretroviral activity, with resistant HIV developing relatively slowly.
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PMID:Tenofovir: Gilead applies for approval; expanded access liberalized. 1156 59

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor PIs alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral; neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agents are urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxil fumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in both resting and activated peripheral blood mononuclear cells that permits once daily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.
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PMID:An introduction to nucleoside and nucleotide analogues. 1167 69

Advice from the Food & Drug Administration and the European Medicines Commission indicates that tenofovir is likely to be licensed shortly for use in patients failing antiretroviral therapy as part of a regimen constructed by the clinician. Tenofovir is a nucleotide (NtRTI) that acts in a similar way to nucleoside analogues by inhibiting reverse transcriptase, producing similar HIV plasma viral load fall. In use up to 48 weeks it appears to be safe without evident toxicity. It has particular value because it has activity against many HIV viruses with mutations which render them insensitive to other nucleoside analogues. Its eventual optimal role in treatment, particularly whether it should be part of a first line regimen, awaits the outcome of further studies.
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PMID:The potential place of tenofovir in antiretroviral treatment regimens. 1177 98

Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 microM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 microM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 microM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity.
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PMID:Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. 1185 Feb 53

Clinical studies with tenofovir disoproxil fumarate, an oral prodrug of the nucleotide analog tenofovir, recently approved for the treatment of HIV, have demonstrated antiviral activity and good tolerability in HIV-infected patients. In order to better understand the cytotoxicity profile of tenofovir relative to the other nucleoside reverse transcriptase inhibitors (NRTIs), the in vitro effects of these agents were evaluated in various human cell types. Tenofovir inhibited the proliferation of liver-derived HepG2 cells and normal skeletal muscle cells with CC(50) values of 398 and 870 microM, respectively. In comparison, ZDV, ddC, ddI, d4T, and abacavir all showed lower CC(50) values in these two cell types. Evaluation of hematopoietic toxicity revealed that tenofovir was less cytotoxic towards erythroid progenitor cells (CC(50)>200 microM) than ZDV, d4T, and ddC (CC(50)=0.06-5 microM). Despite some degree of donor-to-donor variability, the inhibitory activity of the tested NRTIs against myeloid cell lineage, in the order of decreasing severity, was consistently ddC>ZDV>d4T>tenofovir>3TC. Finally, tenofovir showed substantially weaker effects on proliferation and viability of renal proximal tubule epithelial cells than cidofovir, a related nucleotide analog with the potential to induce renal tubular dysfunction. In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease.
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PMID:Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors. 1188 56


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