Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term use of combination therapy against human immunodeficiency virus type (HIV-1) provides strong selective pressure on the virus, and HIV-1 variants that are resistant to multiple inhibitors have been isolated. HIV-1 variants containing amino acid substitutions within the coding region of HIV-1 reverse transcriptase (RT), such as the 3'-azido-3'-deoxythymidine (AZT)-resistant variant AZT-R (M41L/D67N/K70R/T215Y/K219Q) and a variant containing an insertion in the fingers domain (S69SGR70/T215Y), are resistant to the nucleoside RT inhibitor (NRTI) AZT because of an increase in the level of excision of AZT monophosphate (AZTMP) from the primer. While rare, variants have also been isolated which contain deletions in the RT coding region. One such virus, described by Imamichi et al. (J. Virol 74:10958-10964, 2000; J. Virol. 74:1023-1028, 2000; J. Virol. 75:3988-3992, 2001), contains numerous amino acid substitutions and a deletion of codon 67, which we have designated the Delta67 complex of mutations. We have expressed and purified HIV-1 RT containing these mutations. We compared the polymerase and pyrophosphorolysis (excision) activity of an RT with the Delta67 complex of mutations to wild-type RT and the two other AZT-resistant variants described above. All of the AZT-resistant variants we tested excise AZTMP and 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA [tenofovir]) from the end of a primer more efficiently than wild-type RT. Although the variant RTs excised d4TMP less efficiently than AZTMP and PMPA, they were able to excise d4TMP more efficiently than wild-type RT. HIV-1 RT containing the Delta67 complex of mutations was not able to excise as broad a range of NRTIs as the fingers insertion variant SSGR/T215Y, but it was able to polymerize efficiently with low concentrations of deoxynucleoside triphosphates and seems to be able to excise AZTMP and PMPA at lower ATP concentrations than AZT-R or SSGR/T215Y, suggesting that a virus containing the Delta67 complex of mutations would replicate reasonably well in quiescent cells, even in the presence of AZT.
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PMID:Effects of the Delta67 complex of mutations in human immunodeficiency virus type 1 reverse transcriptase on nucleoside analog excision. 1533 32

An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4(+) T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC(50)]) was determined by treating HIV-infected MO-DC/CD4(+)-T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interleukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC(50) values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC(50), resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides.
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PMID:A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides. 1538 20

The acyclic nucleoside phosphonates [HPMPC: cidofovir, Vistide; PMEA: adefovir dipivoxil, Hepsera; and PMPA: tenofovir, Viread] have proven to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections, for example, cidofovir against herpesvirus [herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus type 6, 7 and 8), polyoma-, papilloma-, adeno- and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus and orf) infections; adefovir against herpesvirus, hepadnavirus [human hepatitis B virus] and retrovirus [HIV type-1 and 2, simian immunodeficiency virus and feline immunodeficiency virus] infections; and tenofovir against both hepadna- and retrovirus infections. Cidofovir has been officially approved for the treatment of cytomegalovirus retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) for the treatment of HIV infections (i.e., AIDS) and adefovir dipivoxil for the treatment of chronic hepatitis B.
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PMID:Potential of acyclic nucleoside phosphonates in the treatment of DNA virus and retrovirus infections. 1548

Tenofovir disoproxil fumarate (Viread) is the first nucleotide analog reverse transcriptase inhibitor to be approved by the Food and Drug Administration for the treatment of HIV infection. It is a potent agent with a long intracellular half-life that allows for once-daily dosing. It has been well-tolerated in clinical trials to date, without evidence of long term toxicity, including the mitochondrial toxicity that has been associated with some nucleoside analog reverse transcriptase inhibitors. Since its approval in October 2001, tenofovir disoproxil fumarate has quickly become a widely used component of antiretroviral regimens for both treatment-naive and -experienced patients.
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PMID:Tenofovir disoproxil fumarate (Viread) for the treatment of HIV infection. 1548 38

(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

Adefovir dipivoxil was recently approved for the treatment of wild-type and lamivudine-resistant hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV infected patients, has recently been shown to also be effective in patients with lamivudine-resistant HBV infection. We therefore compared the two substances in a study of 53 patients defined by high HBV DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance. Thirty-five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir-treated patients showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variations in HBV DNA decline were observed in the adefovir group. Thus at week 48, only 44% of these patients had HBV DNA levels below 10(5) copies/mL in contrast to 100% of the tenofovir-treated patients (P = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir-treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection.
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PMID:Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. 1588 36

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 disoproxil fumarate (TDF) has been anecdotally associated with isolated hypophosphatemia (HP) as well as proximal tubular toxicity and renal dysfunction in which HP has consistently been a feature. Consequently, routine phosphate measurements in TDF recipients have been recommended. We identified and compared the frequency of HP in TDF recipients with that in non-TDF recipients; assessed the reproducibility of HP; identified the incidence of renal dysfunction in hypophosphatemic patients; and evaluated associations between HP and host, HIV infection, or treatment factors. This prospective observational study measured serum phosphate, urea, and creatinine in HIV-positive individuals among the following treatment groups: TDF-containing highly active antiretroviral therapy (HAART, group A), TDF-sparing HAART (group B), HAART naive (group C), and off HAART but treatment experienced (group D). Phosphate measurements were obtained in 252 patients. Seventy-two percent of patients prescribed TDF received a phosphate measurement. The frequency of HP in groups A, B, C, and D was 31%, 22%, 10%, and 14%, respectively. Seventy-eight percent of phosphate measurements were reproducible. Kaletra (P = 0.016) administration and duration of antiretroviral therapy (P = 0.023) were independently associated with HP, but elevated creatinine and urea or use of TDF was not. The etiology of HP seems to be multifactorial and unrelated to TDF or renal dysfunction. This questions the utility of routine phosphate testing, in isolation, in TDF recipients.
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PMID:Serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice. 1573 48

In order to study the inhibitory effect of various reverse transcriptase inhibitors (RTIs) on cell-free HIV, we adapted a recently described in vitro system, based on co-cultures of dendritic cells and resting CD4 T cells, modelling early target cells during sexual transmission. The compounds tested included the second-generation non-nucleoside RTI (NNRTI) TMC-120 (R147681, dapivirine) and TMC-125 (R165335, travertine), as well as the reference nucleoside RTI AZT (zidovudine), the nucleotide RTI PMPA (tenofovir) and the NNRTI UC-781. The virus strains included the reference strain HIV-1Ba-L and six primary isolates, representative of the HIV-1 group M pandemic. They all display the non-syncytium-inducing and CCR5 receptor-using (NSI/R5) phenotype, important in transmission. Cell-free virus was immobilized on a poly-L-lysine (PLL)-treated microwell plate and incubated with compound for 1 h. Afterwards, the compound was thoroughly washed away; target cells were added and cultured for 2 weeks, followed by an extended culture with highly susceptible mitogen-activated T cells. Viral production in the cultures was measured on supernatant with HIV antigen ELISA. Negative results were confirmed by showing absence of proviral DNA in the cells. TMC-120 and TMC-125 inhibited replication of HIV-1Ba-L with average EC50 values of 38 nM and 117 nM, respectively, whereas the EC50 of UC-781 was 517 nM. Complete suppression of virus and provirus was observed at compound concentrations of 100, 300 and 1000 nM, respectively. Inhibition of all primary isolates followed the same pattern as HIV-1Ba-L. In contrast, pre-treating the virus with the nucleotide RTI PMPA and AZT failed to inhibit infection even at a concentration of 100000 nM. These data clearly suggest that NNRTIs inactivate RT enzymatic activity of different viral clades (predominant in the epidemic) and might be proposed for further testing as a sterilizing microbicide worldwide.
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PMID:Pre-incubation of cell-free HIV-1 group M isolates with non-nucleoside reverse transcriptase inhibitors blocks subsequent viral replication in co-cultures of dendritic cells and T cells. 1586 20

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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