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

The appearance in the clinic of two to three new antiretroviral agents yearly since 1995 has permitted unprecedented advances in HIV treatment. This remarkable pace of drug development is a testimony to an extraordinary international effort involving scientists, clinicians, governments, community activists and industry dedicated to the rapid and safe development of novel therapies. New drugs present the opportunity to improve HIV therapy. They also create an enormous challenge to the clinician, who must constantly assimilate data on new drugs and incorporate this information into practical management strategies. Combination therapy has proven the most effective approach to treat HIV disease. The profound and sustained viral suppression achievable with combinations such as indinavir (IDV), lamivudine (3TC) and zidovudine (ZDV) have resulted in a dramatic shift in HIV treatment paradigms over the last year. The full potential of combination therapy with available drugs has yet to be realized as only a limited number of the possible combinations incorporating new drugs have been fully tested. Even drugs available for many years may have untapped potential. Didanosine (ddI) and stavudine (d4T), once thought to be contraindicated in combination because of their overlapping peripheral neuropathy toxicity, have proven well tolerated and effective. Combination therapy can increase antiviral suppression, prevent drug resistance, optimize drug exposure and simplify dosing, but it can also result in pharmacologic antagonism, subtherapeutic drug concentrations and unexpected toxicities. Clinical studies have confirmed in vitro studies showing pharmacologic antagonism for the combination of ZDV and d4T. Combining protease inhibitors with each other or with non-nucleoside reverse transcriptase inhibitors is complicated by effects both classes of drugs have on drug metabolism and clearance. These observations underline the importance of carefully conducted clinical studies to characterize safety, pharmacokinetics and efficacy of combination therapies. In this review, we will first summarize the clinical profile of new drugs which either became commercially available last year [nelfinavir, nevirapine, delavirdine (DLV)] or are in the late stages of clinical development (DMP-266, abacavir and 141W94). Later we will summarize new data on nucleoside, protease inhibitor and non-nucleoside reverse transcriptase combination regimens. Finally, we will briefly mention new drugs in early stages of development.
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PMID:New antiretrovirals and new combinations. 963 99

In a set of 42 antiretroviral naive HIV-1 infected persons who were treated with either Zidovudine (AZT) monotherapy, or a combination of AZT + ddC (Zalcitabine) or AZT + ddI (Didanosine), the HIV-1 DNA load was measured by competitive polymerase chain reaction (PCR) and related to the HIV-1 RNA load in plasma, the CD4+ counts and to clinical markers. The question was whether a reduction in the cellular HIV-1 DNA level contributes to clinical benefit, as predicted by a lasting response in HIV-1 RNA levels in plasma. No significant decline relative to baseline in HIV-1 DNA load was found in the AZT monotherapy arm. In this arm the differences from baseline for both HIV-1 RNA load and CD4+ T cell counts were small and transient. In both combination therapy arms, the maximum mean decline in HIV-1 DNA load was 0.6 log and it never differed significantly from baseline. This is in contrast to plasma HIV-1 RNA load that declined earlier and steeper (mean of 1.5 and 1.9 log for AZT + ddC and AZT + ddI, respectively) and that remained significantly below baseline for 80 weeks. Although 9 of 42 (32%) of the patients under combination therapy had prolonged decreased plasma RNA levels, the proviral HIV-1 DNA remained present in the cells throughout the total follow-up of 144 weeks. In conclusion, combination therapy showed better laboratory parameter responses than AZT monotherapy, in agreement with the clinical data. The HIV-1 DNA sequences did not disappear in any of the patients, heralding renewed active infection after cessation of therapy.
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PMID:Cellular proviral HIV type 1 DNA load persists after long-term RT-inhibitor therapy in HIV type 1 infected persons. 971 20

Didanosine (Videx, ddI) has been shown to be an effective agent in the treatment of HIV disease. However, patients have had difficulties adhering to didanosine preparations due to taste aversion and/or associated nausea. The efficacy of didanosine may, therefore, be compromised. This is of concern to clinicians who seek to promote patient adherence to medication regimes and to foster the quality of patient well-being. In this study, focus groups were used to gather exploratory data about patient (n = 15) response to the new mandarin orange didanosine preparation. Data were audiotaped, transcribed verbatim, and systematically analyzed by the investigators using inductive techniques. Findings provide information regarding client evaluation of the new didanosine preparation and patterns of usage. Although clients generally find the mandarin orange preparation more tolerable, they describe engaging in numerous strategies aimed at attenuating what they experience as the inconvenience of taking the medication. Mental tricks, systematic restructuring of daily routines and environment, and dietary schemes were among the strategies devised by patients through trial and error to self-promote their adherence.
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PMID:Patient appraisal of mandarin orange didanosine: implications for adherence and well-being. 1039 67

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.
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PMID:Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3. 1053 45

Hydroxyurea inhibits cellular ribonucleotide reductase, resulting in decreased pools of dNTPs and thus inhibition of DNA synthesis. Studies in vitro have shown that hydroxyurea reduces dNTP pools in cells infected with human immunodeficiency virus type 1 (HIV-1), inhibiting HIV-1 DNA synthesis in infected quiescent and activated primary human lymphocytes and macrophages. Hydroxyurea also potentiates the activity of nucleoside reverse transcriptase inhibitors (NRTIs): the activated triphosphate forms of NRTIs compete with naturally occurring dNTPs for incorporation into nascent viral DNA during reverse transcription. A synergistic effect is observed between hydroxyurea and didanosine (2',3'-dideoxyinosine; DDI). This combination exerts persistent suppression of HIV-1 replication without evidence of viral rebound for over 1 year in HIV-1-infected patients. Didanosine-resistant HIV-1 mutants retain sensitivity to didanosine in the presence of hydroxyurea. The incorporation of didanosine triphosphate by resistant reverse transcriptase is increased in the context of the hydroxyurea-induced depletion of dATP. Although hydroxyurea has a reduced effect on dNTPs competing with the triphosphate forms of pyrimidine NRTIs, it appears to augment the anti-HIV-1 activity of these agents by increasing their intracellular phosphorylation; this may be of particular interest for salvage strategies given recent data indicating disruption of NRTI phosphorylation with specific NRTI treatment regimens. Finally, by exerting a cytostatic effect on CD4 and CD8 T lymphocytes, hydroxyurea may (i) reduce HIV-1 replication by decreasing CD4 T cell proliferation; and (ii) prevent the exhaustion of CD8 T cell populations that may occur as a result of excessive activation in the context of HIV-1 infection.
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PMID:Hydroxyurea: mechanisms of HIV-1 inhibition. 1072 6

The effect of food on didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in similar areas under the concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8 microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3 liters/hr/m2) were similar, but these values in children are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of didanosine was highly variable in children but similar in the presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected children.
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PMID:Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team. 1077 27

Orally administered anti-HIV drugs must be adequately and consistently absorbed for therapy to be successful. This review discusses the barriers to achieving oral bioavailability for the currently available anti-HIV drugs. Most reverse transcriptase inhibitors have good oral bioavailabilities. Didanosine bioavailability could be reduced by acid instability, first-pass hepatic metabolism, and possibly poor intestinal permeation. Bioavailability of zidovudine is also reduced by first-pass metabolism. The non-nucleoside reverse transcriptase inhibitors have oral bioavailabilities most probably limited by poor aqueous solubility. For each of the currently marketed HIV protease inhibitors, solubility, intestinal permeability, and first-pass metabolism could contribute to reducing oral bioavailability. The intestinal permeabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much greater than permeation in the absorptive direction for indinavir, nelfinavir, ritonavir, and saquinavir. The mechanisms of secretory intestinal transport are reviewed, and the factors that may influence the impact of secretory transport in vivo are considered.
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PMID:P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs. 1083 70

Dideoxynucleosides currently in use for anti-HIV therapy have been found to be inefficient in passing through the blood-brain barrier to enter and maintain therapeutic drug levels in brain, a very significant reservoir of HIV. The low bioavailability of these drugs combined with the bone marrow toxicity of AZT (3'-azido, 3'-deoxythymidine, Zidovudine), resulting in anemia and leukopenia, pancreatitis with ddI (2',3'-dideoxyinosine, Didanosine) and painful peripheral neuropathy in case of ddC (2',3-dideoxycytosine, Zalcitabine) are the limiting factors in their use. In addition, the emergence of strains of HIV resistant to AZT, the most commonly used drug, further restricts its use. Thus the control of AIDS and its complications, needs special therapeutic approaches to combat the disease. In order to overcome these limitations, AZT and ddI have been synthesized as ester-linked ceramide- and phosphatidylcholine-linked prodrugs possessing therapeutic attributes lacking in the parent compounds. There is greater uptake and longer retention of these prodrugs in NIH/3T3 cells in vitro. Pretreatment with our prodrugs blocked infection of these cells by Moloney murine leukemia virus (M-MuLV) for an extended period, which the parent drugs failed to do. When human CD4+ HeLa cells were continuously exposed to the AZT prodrug, subsequent infection of these cells by HIV was blocked. Similar results were obtained with NIH/3T3 cells exposed to M-MuLV. AE(6)C, a prodrug of AZT linked to ceramide via a cleavable ester bond and a six carbon linker, was less toxic to both mouse and human bone marrow progenitor cells than free AZT. Most significantly, the prodrugs concentration was greater and the retention longer, in well known sanctuaries for HIV, such as the brain, testes and thymus.
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PMID:Improved uptake and retention of lipophilic prodrug to improve treatment of HIV. 1083 73

Didanosine (ddI) is used in the treatment of HIV-1 infection alone and in combination with azidothymidine (AZT). When combined with AZT, patients exhibit improved patterns of surrogate markers after sequential combination regimens of ddI and AZT compared to either drug monotherapy. We have investigated the biochemical mechanism(s) of this synergistic drug combination in human PBMC cells and in human T-cell lines sensitive and resistant to AZT due to lack of thymidine kinase (TK). DdI is preferentially activated to its triphosphate anabolite, ddATP, at 3:1 ratio in human T-lymphocytes compared to monocytes from the same individual. There are no apparent differences in the intracellular concentrations of ddATP in Jurkat/0 and Jurkat/AZT-10, an AZT resistant human T-cell line, when ddI is administered alone or in combination with AZT, hence there appears to be a case of collateral sensitivity. Intracellular increases of AZTTP concentrations in patient's PBMC cells have been determined clinically after AZT alone and in a combination regimen with ddI. A stochastic biochemical model has been developed that estimates the velocity of HIV-RT under uninhibited and inhibited conditions by the active anabolites, AZTTP and ddATP. This model provides a rational explanation for the greater inhibition of HIV-RT in the presence of both inhibitors, AZTTP and ddATP, as compared to the presence of either anabolite triphosphate alone. Expanding this model to describe the inhibition of HIV-RT in the presence of three competitive inhibitors, AZTTP, ddATP and 3TCTP demonstrated that the presence of these HIV-RT inhibitors resulted in an even greater inhibition of this viral enzyme necessary for HIV integration and replication. Hence, a more effective inhibition of HIV-RT enzyme is achieved by the combination of the three drugs, AZT, ddl and 3TC. In an effort to verify this model with experimental data the kinetics of HIV-RT were studied in the absence and after inhibition by AZTTP or ddATP alone, both AZTTP + ddATP or AZTTP + ddATP + 3TCTP. Treatment of HIV-RT with high concentrations of these triphosphate inhibitors, as high as 3Kis, inhibited this enzyme to greater than 90% of untreated control. However, a small percentage of residual HIV-RT, 6%, was uninhibited even after exposure to 3Ki concentrations of each inhibitor. These studies strongly suggested that: 1) AZT plus ddI or AZT plus ddI plus 3TC are synergistic at the active anabolite level against HIV-RT; 2) the combination of the three nucleoside analog drugs (AZT, ddI 3TC) is needed for more effective inhibition of HIV-RT; 3) that the combination of the triphosphates at concentrations much greater than those pharnacologically achieved in T-Cells or PBMC under treatment conditions did not inhibit completely HIV-RT. Hence, the three nucleoside HIV-RT inhibitors must be combined with other classes of antiviral drugs or T-cell specific inhibitor drugs.
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PMID:Pharmacodynamic studies (PD) of didanosine (ddI) alone and in combination with azidothymidine (AZT) in human T-cells; a stochastic biochemical approach to antiretroviral nucleoside drug combination in inhibiting HIV-reverse transcriptase (RT). 1090 70

Factors affecting patient adherence to therapy, such as frequent daily dosing and complex dosing schedules, are widely understood to be key obstacles to the durability of effective anti-HIV therapy. Didanosine, a nucleoside analogue reverse transcriptase inhibitor (NRTI) that is a core component of combination antiretroviral regimens, is currently indicated for twice-daily dosing. However, the active metabolite of didanosine (2',3'-dideoxyadenosine-5'-triphosphate) has a long intracellular half-life that supports the use of didanosine in a more patient-friendly, once-daily dosing schedule. Clinical studies in which didanosine was administered either once or twice daily, as monotherapy or in combination with another NRTI, have demonstrated the equivalence of both dosing schedules, with respect to safety and tolerability, virologic and immunologic endpoints, and short-term clinical effects (e.g., weight gain). Preliminary results from recent studies support the clinical efficacy and utility of once-daily didanosine in combination antiretroviral regimens that provide maximal drug exposure, while allowing for once- or twice-daily dosing of all component drugs.
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PMID:Didanosine once daily: potential for expanded use. 1110 Oct 51

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