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

Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety and efficacy of adefovir dipivoxil monotherapy, a randomized, double-blind, placebo-controlled study was initiated involving 72 subjects with moderately advanced HIV disease. Subjects were randomly assigned in a 2:1 ratio to receive adefovir dipivoxil or placebo as a once-daily oral dose for 6 weeks, followed by 6 weeks of open-label adefovir dipivoxil. Two dose levels were studied (125 mg and 250 mg). Adefovir dipivoxil was determined to be safe and well-tolerated when administered for 12 weeks. At week 6, changes in absolute CD4 T cell levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with placebo. These effects were sustained through 12 weeks of treatment. As determined by standard RNA sequencing techniques, only 1 of the 24 subjects who received adefovir dipivoxil (125 mg/day) developed any genotypic change from baseline.
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PMID:The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults: a randomized, double-blind, placebo-controlled trial. 939 63

Adefovir (PMEA, 9-(2-phosphonomethoxyethyl)adenine), an acyclic nucleoside phosphonate analogue is active against retroviruses, hepadnaviruses and herpesviruses. Adefovir dipivoxil, an orally bioavailable prodrug of adefovir is currently in phase III clinical trials for the treatment of HIV and phase II clinical trials for the treatment of HBV infections. PMPA (9-(2-phosphonomethoxypropyl)adenine) is a related acyclic nucleoside phosphonate analogue that has demonstrated potent anti-SIV activity in rhesus macaques and recently has shown marked anti-HIV activity in a phase I clinical study. Since the standard of care for AIDS patients has become combination therapy, the effects of other antiretroviral compounds (d4T, ddC, AZT, ddI, 3TC, nelfinavir, ritonavir, indinavir, and saquinavir) on the anti-HIV activity of adefovir and PMPA were investigated in vitro. Adefovir and PMPA both demonstrated strong synergistic anti-HIV activity in combination with AZT. Adefovir demonstrated minor to moderate synergistic inhibition of HIV replication in combination with PMPA, d4T, ddC, nelfinavir, ritonavir, and saquinavir. PMPA demonstrated minor synergistic inhibition of HIV replication in combination with ddI and nelfinavir (and adefovir). All other combinations showed additive inhibition of HIV replication in vitro. Importantly, no antagonistic interactions were measured for any of the adefovir or PMPA combinations.
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PMID:Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. 944 65

Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses expressing either a K65R or a K70E mutation in reverse transcriptase (RT) have reduced sensitivity to PMEA and that the K70E mutant also has impaired replication capacity in vitro. Genotypic analyses of samples from patients enrolled in a phase I/II clinical trial of adefovir dipivoxil demonstrated that the K70E RT mutation developed in two of 29 patients during extended therapy. To further investigate the molecular mechanisms involved in the resistance to PMEA, we cloned, expressed, and purified HIV-1 RT enzymes carrying either the K65R or K70E and, for comparison, the M184V mutation. The Km values of dNTPs for these mutant enzymes were not significantly altered from wild-type RT. The Ki values for the K65R mutant were increased from wild-type by 2-5-fold against a variety of inhibitors, whereas the Ki values for the M184V mutant were increased 12-fold specifically for 2', 3'-dideoxy-3'-thiacytidine (3TC) triphosphate. The Ki values for the K70E mutant were increased for PMEA diphosphate and 3TC triphosphate by 2-3-fold. These results are in agreement with antiviral drug susceptibility assay results. The three recombinant enzymes were also evaluated for their specific activities and processivities. All mutants were reduced in specific activity with respect to wild-type RT. In single-cycle processivity studies, the M184V mutant was, as expected, notably impaired. The K70E mutant was also slightly impaired, whereas the K65R mutant was slightly more processive than wild-type. These results with recombinant K70E RT are consistent with the reduced in vitro replication capacity of the K70E RT mutant of HIV-1 and further demonstrate that the K70E mutation confers minor PMEA and 3TC resistance to HIV-1.
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PMID:Human immunodeficiency virus type 1 reverse transcriptase expressing the K70E mutation exhibits a decrease in specific activity and processivity. 968 70

Adefovir dipivoxil is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir (PMEA), the prototype compound of the acyclic nucleoside phosphonates. It has better oral bioavailability than the parent compound. Adefovir dipivoxil 120mg once daily significantly reduced viral load compared with placebo when added to standard antiretroviral therapy in a 6-month, double-blind study in patients with HIV infection. Viral suppression was maintained during an additional 6-month nonblind extension phase. The drug was most effective in patients with baseline isolates containing the M184V lamivudine resistance mutation according to data from a virological substudy of a large placebo-controlled trial. Adefovir dipivoxil 60mg was as effective as 120mg (both once daily) after 20 weeks' treatment in a randomised double-blind study in antiretroviral-experienced (protease inhibitor-naive) patients. Viral suppression was generally maintained in patients who developed new reverse transcriptase mutations during adefovir dipivoxil monotherapy or combination therapy for up to 12 months. No clear pattern of particular clinical resistance mutations has emerged. GI disturbances, hepatic effects and delayed renal abnormalities are the principal adverse events seen with adefovir dipivoxil. Reductions in serum free carnitine levels may occur and coadministration of L-carnitine is recommended.
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PMID:Adefovir dipivoxil. 1049 75

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.
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PMID:A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection. 1060 55

Two trials for adefovir dipivoxil combined with other antiretroviral treatments, GS-96/411 and GS-97/417, are currently recruiting in cities throughout the United States. Adefovir dipivoxil is taken once daily; it has shown modest activity against HIV; and it is known to be active against CMV, hepatitis B, HHV6, and Epstein-Barr virus. Both studies last 48 weeks. Patients will receive their viral load results after weeks 8, 20, 32, and 48. All of the drugs and tests are free. Details of each study and contact information are provided.
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PMID:Adefovir dipivoxil trials: CD4 100-500, protease inhibitor naive. 1136 24

Adefovir dipivoxil (Preveon), a nucleotide analog and a prodrug of PMEA, has been approved for a limited expanded access program for patients who have failed approved treatments. Earlier results from phase I/II trials reveal Preveon has modest anti-HIV activity. Preveon is active against virus that has developed resistance to AZT, 3TC, and other approved nucleoside analogs. To be eligible, patients must be at least 13 years old, failed at least two nucleoside analog reverse transcriptase inhibitors and one protease inhibitor, and within the last 2 months have had a CD4 count of 50 or less and a viral load of at least 30,000 by PCR or at least 15,000 by bDNA. The program will supply only Preveon and the L-carnitine. The AIDS community has expressed concerns about the drug's potential kidney toxicity with long-term use, a condition that becomes clinically evident usually after the first 4 months, possibly leading physicians into complacency in performing regular laboratory tests after that time. The study requires monthly urine testing, including serum creatinine, urine protein, and urine glucose. Another concern is the study's CD4 and viral load restrictions; AIDS advocates believe the restrictions do not allow physicians flexibility in their drug treatment decision-making.
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PMID:Adefovir dipivoxil (Preveon) expanded access begins. 1136 18

Gilead Sciences has seen beneficial results from two trials of adefovir dipivoxil (Preveon) in the treatment of HIV. An additional trial of adefovir dipivoxil was a success, dramatically reducing hepatitis B viral load by 99.99 percent. GS 411 assigned treatment-naive patients to one of five regimens that included indinavir (Crixivan) and adefovir. The results suggest that adefovir, which is metabolized differently and has different side effects, may be an alternative for some nucleoside analogs. GS 408 added adefovir to the regimens of treatment-experienced patients and showed a marked decrease in viral load for those patients who used adefovir versus a placebo. Adefovir dipivoxil may also be used effectively against other viruses such as CMV, HHV6 and Epstein-Barr. Long-term effectiveness in controlling the HIV virus has yet to be determined.
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PMID:Adefovir dipivoxil (Preveon) new results with hepatitis B, HIV. 1136 89

Four new drugs have been developed to overcome the limitations of the currently available anti-HIV drugs, including inconvenient schedules, side effects, and drug interactions. It is hoped that abacavir, efavirenz, adefovir dipivoxil, and amprenavir will be widely available in the near future. Abacavir, a nucleoside reverse transcriptase inhibitor with a twice-daily schedule, offers good bioavailability and generally mild side effects. Efavirenz, a non-nucleoside reverse transcriptase inhibitor with a once daily schedule, may produce side effects such as rash and dizziness. Adefovir dipivoxil, a nucleotide analog with once daily dosing, can cause carnitine depletion and carnitine supplementation is recommended. Amprenavir, a protease inhibitor with twice-daily dosing, has rather mild side effects. Information on efficacy, availability, and resistance for each of these drugs is given.
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PMID:Antiretroviral agents: the next generation. 1136 27

The 38th Interscience Conference on Antimicrobial Agents and Chemotherapy featured information on new antiretroviral treatments, changes in dosing, and new vaccine information. Adefovir dipivoxil (Preveon) is a new nucleoside reverse transcriptase inhibitor that is administered once daily. A study of adefovir dipivoxil is described and the side effects are detailed. A clinical trial of the protease inhibitor Nelfinavir (Viracept) has shown that dosing twice a day may be as effective as the currently prescribed three times a day. Since lower dosing tends to increase a patient's adherence to treatment, it may have a long-term positive effect on treating HIV. Other drug treatments and possible changes in dosing are presented. A pneumococcal vaccine study is described, and it was found that the vaccine did not lead to an increase in viral load. Immunization against Pneumococcus is suggested for all adults who are HIV-infected.
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PMID:Antimicrobial agents and chemotherapy: highlights of the 38th Interscience Conference. 1136 34


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