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PubMedDate not supplied

Combined analysis of two-year follow-up from two open-label randomized trials comparing efficacy of three nucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1 infection: OzCombo 1 and 2.

PURPOSE: To compare inhibition of HIV replication, improvements in CD4+ T-cell counts, metabolic parameters, and body shape changes after 2 years of assigned therapy in OzCombo patients. METHOD: Study participants were those who were recruited into the open-label OzCombo 1 (1996/1997) and OzCombo 2 (1997/1998) trials. Patients in OzCombo 1 were randomized to receive indinavir in combination with zidovudine+lamivudine (AZT+3TC; n = 35), stavudine (d4T)+3TC (n = 34), or d4T+didanosine (ddI) (n = 37). OzCombo 2 patients were randomized to the same nucleoside reverse transcriptase inhibitor (NRTI) backbones with nevirapine (n = 20, 22, 23, respectively). The mean time-weighted changes from baseline in CD4 T-cell count/mL, HIV RNA (log copies/mL plasma), and proportions with detectable viral load (<500 copies plasma HIV RNA/mL) between NRTI arms over 2 years were compared by formal meta-analysis. A cross-sectional study of metabolic and body shape complications was also undertaken. RESULTS: For the comparison of d4T+3TC and d4T+ddI to AZT+3TC, mean differences in time-weighted change from baseline in CD4 T-cell count/microL and log copies HIV RNA/mL adjusted for baseline CD4+ T-cell and HIV RNA counts were: -44 (p =.08) and -14 (p =.56) cells/microL and -0.1 (p =.40) and -0.1 (p =.6) copies/mL. Odds ratios for detectable viral load in the last study quarter were 0.6 (p =.44) and 1.0 (p =.95). The mean percent leg fat was lower in the d4T+3TC and d4T+ddI than the AZT+3TC arm (mean difference 5.1% [p =.07] and 7.6% [p =.02], respectively). CONCLUSION: For all regimens, virological control and immunological response were maintained over 2 years. Regimens containing d4T and particularly d4T+ddI were significantly associated with increased peripheral fat loss compared with AZT+3TC.

Adipose Tissue↗
PubMed2001

2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

Anti-HIV Agents↗
PubMed1995

Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication.

HBY 097 [(S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroquinoxaline-2(1H)-thione] was selected from a series of quinoxalines as a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). HBY 097 was shown to be a highly potent inhibitor of HIV-1 induced cell killing and HIV-1 replication in a variety of human cell lines as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against a variety of clinical isolates of HIV-1 including different HIV-1 subtypes and viruses resistant to 3'-deoxy-3'-azidothymidine. Mutant reverse transcriptases which arise as a consequence of treatment with other nonnucleoside inhibitors of HIV-1 reverse transcriptase were still inhibited by HBY 097 at relatively low concentrations. An HIV-1MN variant resistant to inhibition by HBY 097 displayed in the reverse transcriptase gene a mutation causing a substitution at position 190 of a glutamic acid for a glycine residue (G190 --> E), which is characteristic for quinoxaline derivatives. The drug was demonstrated to possess a favorable toxicity profile and to show good oral bioavailability in both mice and dogs. As a consequence of its outstanding properties, HBY 097 was selected for further development and is at present undergoing clinical trials.

Animals↗
PubMedDate not supplied

Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices.

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.

Animals↗
PubMed2004

HIV-1 reverse transcriptase inhibitors: current issues and future perspectives.

One of the major advances in the recent history of the treatment of HIV infections has been the development of different classes of effective antiretroviral drugs. In particular, the reverse transcriptase (RT) inhibitors still represent the majority of the clinically used anti-HIV drugs and constitute the main backbone of currently employed combinatorial regimens. Highly active antiretroviral combination chemotherapy (HAART), combining RT and protease inhibitors, has proven the most effective approach to treat HIV disease, since it has been shown to markedly suppress viral replication and appearance of drug resistance for a relatively long period. These therapies, however, do not constitute a definitive cure, since they are not able to completely eradicate the virus from the infected individual. Beside drug toxicity problems, the emergence of drug resistance associated with the particular regimen employed further complicates the situation. This review will summarise the most recent achievements, as well as the future directions in the development of novel anti-RT compounds.

Animals↗
PubMedDate not supplied

Anti-AIDS agents, 1. Isolation and characterization of four new tetragalloylquinic acids as a new class of HIV reverse transcriptase inhibitors from tannic acid.

Four new tetragalloylquinic acids, 3,5-di-O-galloyl-4-O-digalloylquinic acid, 3,4-di-O-galloyl-5-O-digalloylquinic acid, 3-O-digalloyl-4,5-di-O-galloylquinic acid, and 1,3,4,5-tetra-O-galloylquinic acid, were isolated and characterized from a commercial tannic acid as a new class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitor. Compounds 2, 3, and 4 inhibit HIV RT activity 90, 89, and 84% at 100 microM and 73, 70, and 63% at 30 microM, respectively. Compounds 2-5 also inhibit the HIV growth in cells in the range of 61-70% with low cytotoxicity at 25 microM. The HIV cell growth inhibitory effects of these compounds at 25 microM and 6.25 microM (44-57%) are comparable to their effects against the HIV RT at 30 microM and 10 microM, respectively. The inhibitory effect of 3 against DNA polymerases indicates that the selective antiviral action of 3 is determined by more than its action with HIV RT.

Antiviral Agents↗
PubMedDate not supplied

Stavudine in the face of cross-resistance between HIV-1 nucleoside reverse transcriptase inhibitors: a review.

Despite the current availability of over 15 antiretroviral drugs, diminishing antiretroviral options due to drug cross-resistance constitute a real challenge beyond first-line therapy. Although stavudine (d4T) shares several resistance mutations with other drugs in its class -i.e. nucleoside analogue mutations (NAMs)- literature regarding the actual impact of NAMs on HIV-1 resistance to d4T is conflicting. Several studies conducted over the past few years have, however, shown that the frequency with which d4T selects NAMs is much lower than using zidovudine (AZT), particularly when combined with lamivudine (3TC). In the latter case, NAMs have been found in less than 5% of cases after more than 12 weeks of therapy. In vitro studies have also shown that the impact of d4T on phenotypic drug susceptibility is much lower than that of AZT, with similar genotypic profiles. Few clinical trials have attempted to define a clinically relevant cut-off for phenotypic resistance to d4T. The results of these trials differ considerably and are highly dependent on the studied population. Nonetheless, these data help to clarify the strategic use of d4T in antiretroviral therapy, and to determine the best sequencing options for nucleoside reverse transcriptase inhibitors.

Anti-HIV Agents↗
PubMed2004

High frequency of selection of K65R and Q151M mutations in HIV-2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen.

The objective of the study was to determine retrospectively which substitutions in the reverse transcriptase (RT) gene are selected in vivo during nucleoside RT inhibitors (NRTI) containing regimen in HIV-2 infected subjects. Thirty-four HIV-2 patients having received NRTI-containing regimen with available specimens and amplifiable RT gene were studied. Analyses of RT gene were undertaken after a median NRTI exposure of 51 months (range: 5-128). Mutations at positions known to be involved in HIV-1 resistance were observed in 26/34 patients. Selection of Q151M mutation was observed in nine out of 34 isolates (26%) after a median NRTIs exposure of 41 months (range: 12-77). In 8/9 cases, Q151M mutation was associated with other substitutions at positions known to be involved in HIV-1 resistance: K65R (n = 6), D67N (n = 1), N69S or T (n = 2), K70R (n = 3), M184V (n = 4), S215Y (n = 1). Compared with HIV-1 infection, there is a high frequency of selection of Q151M mutation in HIV-2 infected patients receiving various combinations of NRTIs. In these highly thymidine analogue pretreated patients, the selection of thymidine analogue mutations was low suggesting that the pathway to resistance is very different between these two viruses.

Anti-HIV Agents↗
PubMed2005

Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma.

CONTEXT: Two classes of repeated genomic elements, retrotransposons and endogenous retroviruses, encode for endogenous nontelomeric reverse transcriptase (RT), a gene that is down-regulated in differentiated cells but is highly expressed in embryonic and transformed tissues. Two nonnucleosidic RT inhibitors, efavirenz and nevirapine, currently used in HIV treatment, reversibly down-regulate tumor growth and induce differentiation in several human tumor cell models. OBJECTIVES: Aggressive biological behavior and loss of specific thyroid cell functions, such as thyroglobulin, thyroid peroxidase, TSH receptor, Na/I symporter expression, and iodine uptake are features of anaplastic thyroid cancer. Thus, we evaluated the use of RT inhibitors as a potentially differentiating and molecular-targeted treatment of this neoplasm. RESULTS: Our findings showed that nevirapine and efavirenz reversibly inhibit cell proliferation without triggering cell death in the undifferentiated thyroid carcinoma ARO and FRO cells, which exhibited high levels of endogenous RT activity. Inhibition of cell growth was correlated with accumulation of cells in the G0/G1 phase of the cell cycle, with a concomitant decrease in the S phase. Moreover, treated cells demonstrated a differentiated phenotype and a significant reprogramming of gene expression characterized by up-regulation of the TSH receptor, thyroglobulin, thyroid peroxidase, and Na/I symporter genes. Interestingly, RT inhibition reestablished the ability to uptake iodine in response to TSH either in vitro or in vivo and reversibly down-regulated tumor growth in mice xenografts of ARO cells. CONCLUSIONS: These findings support the need for clinical trials to clarify whether RT inhibitors may restore the sensitivity to radiometabolic therapy in anaplastic thyroid tumors.

Animals↗
PubMed2006

Possible therapeutic vaccine strategy against human immunodeficiency virus escape from reverse transcriptase inhibitors studied in HLA-A2 transgenic mice.

Mutation of human immunodeficiency virus (HIV) leading to escape from anti-HIV drugs is the greatest challenge to the treatment of HIV infection. High-grade resistance to the nucleoside reverse transcriptase (RT) inhibitor lamivudine (also known as 3TC) is associated with a substitution of valine for methionine at position 184 of RT. This amino acid residue is contained within the HLA-A2-restricted epitope VIYQYMDDL (RT-WT). Here, we sought to determine whether a peptide vaccine could be developed using an epitope enhancement strategy that could induce a cytotoxic T-lymphocyte (CTL) response specific for an epitope containing the drug resistance mutation M184V to exert an opposing selective pressure. RT-WT-specific CTLs developed from HLA-A2 transgenic mice did not recognize the M184V mutation of RT-WT (RT-M184V). However, RT-M184V exhibited higher binding affinity for HLA-A2 than RT-WT. Also, both anchor-enhanced RT-WT (RT-2L9V) and RT-2L9V-M184V-specific CTLs recognized RT-M184V and displayed cross-reactivity to RT-WT. Nevertheless, the CTL repertoire elicited by the epitope-enhanced RT-2L9V-M184V appeared more selective for the RT inhibitor-induced M184V mutation. Peptide vaccines based on such strategies may be worth testing for their ability to exert selective pressure against drug-resistant strains and thus delay or prevent the development of HIV with the M184V resistance mutation.

AIDS Vaccines↗
PubMed2002

A mutation in the 3' region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance.

The Y318F substitution in the 3' region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been linked to nonnucleoside RT inhibitor (NNRTI) resistance in vitro. A systematic search of a large phenotypic-genotypic database (Virco) linked the Y318F substitution with a >10-fold decrease in NNRTI susceptibility in >85% of clinically derived isolates. There was a significant association between Y318F and use of delavirdine (P = 10(-11)) and nevirapine (P = 10(-6)) but not efavirenz (P = 0.3). Site-directed HIV-1 Y318F mutants in an HXB2 background displayed 42-fold-decreased susceptibility to delavirdine but <3-fold-decreased susceptibility to nevirapine or efavirenz. Combinations of Y318F with K103N, Y181C, or both resulted in decreased efavirenz susceptibility of 43-, 3.3-, and 84-fold, respectively, as well as >100- and >60-fold decreases in delavirdine and nevirapine susceptibility, respectively. These results indicate the importance of the Y318F substitution in HIV-1 drug resistance.

3' Untranslated Regions↗
PubMed2005

Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.

In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.

Cell Line↗