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

Like human immunodeficiency virus infection of humans, infection of rhesus macaques with pathogenic simian immunodeficiency virus (SIV) strains typically results in persistent progressive infection, leading to clinically significant immunosuppression. In previous studies, we administered short term anti-retroviral treatment, shortly after intravenous inoculation with SIVsmE660, in an effort to allow immunologic sensitization under conditions not characterized by overwhelming cytopathic infection compromising the developing immune response. We showed that such treatment allowed control of off treatment viremia and was associated with resistance to rechallenge. Control of off treatment viremia was associated, at least in part, with CD8+ lymphocytes, based on in vivo CD8 depletion studies. In the present study, six rhesus macaques were infected intravenously with 100 MID50 of SIVmac239; four then received 30 days of treatment with tenofovir 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA); 20-30 mg/kg, subcutaneously) starting 24 hours post-inoculation. Tenofovir-treated animals showed low (<500 copy Eq/ml) or undetectable (<100 copy Eq/ml) plasma SIV RNA levels during treatment, with undetectable plasma viremia following discontinuation of treatment. Plasma SIV RNA remained <100 copy Eq/ml, even after depletion of CD8+ lymphocytes, 6 weeks after discontinuation of tenofovir treatment. In contrast to untreated infected control animals that showed substantial depletion of CD4+ T cells from gut-associated lymphoid tissues (GALT), tenofovir-treated animals showed sparing of GALT CD4+ T cells both during the treatment period and in the off treatment follow-up period. However, in contrast to earlier results with animals infected with SIVsmE660, in the present study, the animals did not develop readily measurable cellular anti-SIV immune responses, and did not resist homologous rechallenge with SIVmac239, administered 44 weeks after the initial infection. Differences in the animals and virus strains employed may in part account for the differences in results observed. Comparative analysis of virologic and immunologic parameters in this model system may provide important insights for understanding the basis of effective immunologic control of SIV infection.
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PMID:Transient early post-inoculation anti-retroviral treatment facilitates controlled infection with sparing of CD4+ T cells in gut-associated lymphoid tissues in SIVmac239-infected rhesus macaques, but not resistance to rechallenge. 1449 80

Chronic viral hepatitis has emerged as one of the leading causes of morbidity and mortality among HIV-positive patients. These individuals are at risk for aggressive chronic active hepatitis, cirrhosis, and hepatocellular carcinoma, and eventually, death. Currently available therapies for hepatitis B are limited and include interferon-alpha, lamivudine (3TC), and adefovir. Tenofovir (TDF), a recently approved drug for the treatment of HIV, is also active against hepatitis B. We report the case of a HIV-positive patient with liver cirrhosis secondary to chronic hepatitis B virus (HBV) with evidence of resistance to 3TC. The patient was initially accepted as a liver transplant candidate. However, when TDF was added to his treatment, a remarkable virologic and histopathologic improvement was achieved. The patient was subsequently removed from the liver transplant program and has not suffered from any further hepatic complications.
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PMID:Management of chronic hepatitis B in an HIV-positive patient with 3TC-resistant hepatitis B virus. 1458 80

The HIV/AIDS pandemic continues its spread at a rate of over 15,000 new infections every day. Sexual transmission of HIV-1 is the dominant mode of this pandemic spread. For the first time since the disease emerged in the early 1980s, about half the 42 million people now living with HIV/AIDS worldwide are women. Worldwide, more than 90 percent of all adolescent and adult HIV infections have resulted from heterosexual intercourse. The "feminization" of the pandemic largely driven by the social, economic, and biological factors warrants urgent attention particularly for the adolescent female population. In the absence of an effective prophylactic anti-HIV therapy or vaccine, current efforts are aimed at developing intravaginal/intrarectal topical formulations of anti-HIV agents or microbicides to curb the mucosal and perinatal HIV transmission. Microbicides would provide protection by directly inactivating HIV or preventing HIV from attaching, entering or replicating in susceptible target cells as well as dissemination from target cells present in semen or the host cells that line the vaginal/rectal wall. Thus, ideally, anti-HIV microbicides should be capable of attacking HIV from different angles. In addition, a contraceptive microbicide could help prevent unintended pregnancies worldwide. To be a microbicide, these agents must be safe, effective following vaginal or rectal administration, and should cause minimal or no genital symptoms following long-term repeated usage. A safe and efficacious anti-HIV microbicide is not yet available despite the fact that more than 60 candidate agents have been identified to have in vitro activity against HIV, 18 of which have advanced to clinical testing. Targeting HIV entry has been a favored approach because it is the first step in the process of infection and several readily available anionic polymeric products seem to variably interfere with these processes are the primary candidates for potential microbicides. Formulations of some anionic polymeric antiviral agents have been tested at various doses and various durations for safety, tolerability, and acceptability in Phase I/II clinical trials (vaginal, rectal, or penile studies) in HIV-uninfected and/or HIV-infected populations. Current multicenter Phase I/II safety and Phase II/III efficacy studies that are being conducted or planned in different geographical locations by various special interest groups are designed for rapid clinical development of candidate products. The currently marketed detergent-type spermicide, nonoxynol-9 (N-9), has failed in Phase III clinical trials, due to the drug-induced formation of localized genital lesions that might in fact actually promote virus transmission. Alternative "first-generation" microbicides that have undergone Phase I/II safety and tolerability studies in HIV-uninfected and/or HIV-infected volunteers include polymeric viral fusion inhibitors (dextrin sulfate/Emmelle, carrageenans [PC-213, PC-503, PC-515/Carraguard], cellulose sulfate/Ushercell, polystyrene sulfonate, naphthalene sulfonate [PIC 024-4/PRO 2000/5], acidifying gel [Carbomer 974P/BufferGel], Lactobacillus (L. crispatus) suppository/CTV-05, detergent-type dual-function barriers [ACIDFORM, GEDA Plus, SURETE, Glyminox/C31G/Savvy, Invisible Condom], herbal extracts [Praneem], and viral replication inhibitors [PMPA/Tenofovir]. For majority of these products, no information is available regarding their long-term mucosal safety, carcinogenicity potential, bioavailability, or efficacy following their extended vaginal or rectal exposure. The irritative genitourinary symptoms reported for a number of these first-generation products in Phase I clinical trials implies that the "soft" preclinical endpoints for mucosal safety established for the use and development of vaginal spermicides may not be rigorous enough for vaginal and rectal microbicides because of the efficient sexual tra virus diversity, and genetic environment. It is now apparent that sexually transmitted R5 HIV-1 viruses have less positive charge on their surface compared with the R4 HIV-1 viruses, which may limit the anionic polymers as topical microbicides despite extensive clinical trials. Nevertheless, their ongoing clinical trials, reviewed here, using optimized formulations, and special populations in various geographic locations are paving the way for future rigorous clinical testing of "mechanism-based" broad-spectrum anti-HIV microbicides that are currently under intense development. It is anticipated that future microbicide trials will focus on combination of products capable of attacking HIV life cycle at multiple steps intended to increase efficacy, limit cross-resistance as well as minimize microbicide-induced host toxicity.
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PMID:Clinical development of microbicides for the prevention of HIV infection. 1475 90

Tenofovir, also known as PMPA, R-9-(2-(phosphonomethoxypropyl)adenine, is a nucleotide reverse transcriptase (RT) inhibitor. We have determined the crystal structures of two related complexes of HIV-1 RT with template primer and tenofovir: (i) a ternary complex at a resolution of 3.0 A of RT crosslinked to a dideoxy-terminated DNA with tenofovir-diphosphate bound as the incoming substrate; and (ii) a RT-DNA complex at a resolution of 3.1 A with tenofovir at the 3' primer terminus. The tenofovir nucleotide in the tenofovir-terminated structure seems to adopt multiple conformations. Some nucleoside reverse transcriptase inhibitors, including 3TC and AZT, have elements ('handles') that project beyond the corresponding elements on normal dNTPs (the 'substrate envelope'). HIV-1 RT resistance mechanisms to AZT and 3TC take advantage of these handles; tenofovir's structure lacks handles that could protrude through the substrate envelope to cause resistance.
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PMID:Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir. 1510 37

Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a nucleotide (nucleoside monophosphate) analogue with activity against retroviruses, including HIV-1, HIV-2 and hepadnaviruses. Following absorption, tenofovir DF is rapidly converted to tenofovir, which is metabolised intracellularly to its active anabolite tenofovir diphosphate, which is a competitive inhibitor of HIV-1 reverse transcriptase and terminates the growing DNA chain. Tenofovir exerts antiviral effects in a variety of cell types, including resting cells. Tenofovir exhibits longer serum (17 hours) and intracellular (> or =60 hours) half-lives than those of nucleoside analogues, which supports a flexible once-daily administration schedule. The pharmacokinetics of tenofovir are dose-proportional and similar in healthy volunteers and HIV-infected individuals. The oral bioavailability of tenofovir is enhanced by administration with a high-fat meal, but is similar at steady state when administered with or without a typical meal. Tenofovir is not a substrate, inducer or inhibitor of human cytochrome P450 enzymes in vitro or in vivo. Tenofovir DF has been studied with 15 other antiretroviral and other concomitant medications frequently used in the HIV-1-infected population. With the exception of didanosine and atazanavir, which require dosage modifications, no clinically significant drug interactions have been observed with tenofovir DF. The recommended oral dosage of tenofovir DF in adults is 300 mg/day. Tenofovir is eliminated by renal elimination, including tubular secretion; dose-interval adjustments are necessary for tenofovir DF in patients with significant renal impairment. No dosage adjustment of tenofovir DF is necessary in patients with liver disease.
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PMID:Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. 1521 3

Tenofovir disopril fumarate, a new nucleotide analogue against human immunodeficiency virus-1 (HIV-1), can induce hypophosphataemia, the mechanism of which is unclear. Moreover, a renal tubulopathy can occur in long-term treated patients, as observed in 2 HIV-1-infected patients after 12 months of tenofovir therapy, with polyuria-polydipsia, proteinuria, glycosuria and amino-aciduria, which resolved after discontinuation of tenofovir. The risk of renal tubulopathy symptoms in patients on long-term tenofovir therapy should be noted.
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PMID:Tubulopathy consecutive to tenofovir-containing antiretroviral therapy in two patients infected with human immunodeficiency virus-1. 1530 94

The use of tenofovir as part of a HAART regimen has been widely used in HIV-multi-experienced-patients because of its favourable resistance profile. Tenofovir is mainly eliminated by the kidneys and renal toxicity should be carefully monitored. We describe here the case of an HIV-infected patient, without a prior history of renal failure who developed nephrolithiasis and hydronephrosis after starting a tenofovir-containing HAART regimen.
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PMID:Nephrolithiasis and hydronephrosis in an HIV-infected man receiving tenofovir. 1532 33

(1) First-line antiretroviral combinations generally include, in addition to a protease inhibitor or a non nucleoside reverse transcriptase inhibitor, two nucleoside reverse transcriptase inhibitors, namely zidovudine + didanosine, stavudine + lamivudine, or zidovudine + lamivudine. (2) Tenofovir disoproxil (referred to simply as tenofovir below) is a nucleotide HIV reverse transcriptase inhibitor. Previously recommended for second-line treatment in case of virological failure, it is now approved for first-line therapy in adults. (3) This licence extension is based on a double-blind trial comparing tenofovir + lamivudine + efavirenz with stavudine + lamivudine + efavirenz in 602 patients. After 96 weeks, three-quarters of patients had undetectable viral load (<50 copies/ml), and there was no statistically significant difference among the groups. (4) The number of serious adverse effects was similar in the two groups. Relative to the stavudine combinations, there were fewer reports of lipodystrophy (1% versus 12%), fewer peripheral neuropathies (3% versus 10%) and fewer prescriptions of lipid-lowering therapy (2% versus 10%) among patients taking tenofovir. Tenofovir seemed to have a worse effect on renal function and bone metabolism, however. (5) Tenofovir is taken only once a day, but so are didanosine and lamivudine. (6) In practice, there is not yet enough evidence to support the routine use of tenofovir in first-line antiretroviral combinations. Tenofovir is, however, an interesting alternative when stavudine is poorly tolerated.
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PMID:Tenofovir: new indication. For first-line antiretroviral therapy: wait and see. 1549 99

Tenofovir disoproxil fumarate (tenofovir DF; Viread), an ester prodrug of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, is indicated in combination with other antiretroviral agents in the treatment of HIV infection. As a component of an antiretroviral regimen, oral tenofovir DF 300 mg once daily effectively reduces viral load in patients with HIV infection who are treatment-experienced with baseline NRTI resistance mutations or treatment-naive. Tenofovir DF provides a simple and convenient once-daily dosage regimen, and is generally well tolerated and able to produce sustained suppression of viral replication.
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PMID:Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. 1566 81

Tenofovir (TDF) co-administered with didanosine (ddI) 400 mg increases ddI plasma concentrations by up to 60%, raising concerns over toxicity. To limit this interaction, the dosage of ddI may be reduced to 250 mg once daily when co-prescribed with TDF. In this clinical cohort, highly active antiretroviral therapy regimens containing TDF and ddI 250 mg were significantly better tolerated than combinations with TDF and ddI at a dose of 400 mg. Low-dose ddI 250 mg once daily plus TDF as part of antiretroviral therapy was effective.
HIV Med 2005 May
PMID:The durability of virological success of tenofovir and didanosine dosed at either 400 or 250 mg once daily. 1587 80


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