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PubMed2000

Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection.

BACKGROUND: Progressive subcutaneous fat wasting, fat accumulation, dyslipidaemia and insulin resistance in HIV-infected patients on antiretroviral therapy has been attributed to the long-term toxicity of HIV protease inhibitors (PI). More recently, fat wasting has been observed in patients who have never taken a PI, implicating an independent effect of nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy. OBJECTIVES: To determine the relative contribution of NRTI and PI, as well as any other factors, to fat wasting in HIV-infected patients. DESIGN: Longitudinal cohort study involving 277 participants of the Western Australian HIV Cohort Study. METHODS: The time to onset of clinically apparent fat wasting in patients receiving different antiretroviral regimens was compared using standardized clinical criteria. Regional fat measured by dual energy X-ray absorptiometry (DEXA) in 161 patients was also compared. The average rate of percentage fat reduction was estimated in 70 patients who had consecutive DEXA scans at approximately 6-monthly intervals. Multiple confounding factors were considered in the analyses. RESULTS: Progressive subcutaneous fat wasting, indistinguishable from that described in PI-treated patients, does occur in PI-naive, NRTI-treated patients. In patients taking triple combination antiretroviral therapy, age (relative risk = 1.052 per year; P < 0.0001), white race (relative risk = 3.9; P = 0.023), longer duration of dual NRTI therapy prior to addition of PI (relative risk = 1.021 per month; P = 0.0046) and increased cumulative time on stavudine-containing regimens compared with time on zidovudine-containing regimens (relative risk = 1.085 per month; P < 0.0001) are associated with increased risk of fat wasting. Stavudine increases the risk of fat wasting by 265% per year compared with zidovudine. However PI therapy is associated with faster progression to clinically apparent wasting compared with dual NRTI therapy without PI. The results of DEXA scanning supports these clinical data and suggest a non-linear decline in fat over time. CONCLUSIONS: NRTIs do have an independent contribution to fat wasting, but PI are the predominant influence and may act synergistically with NRTIs. NRTIs appear to predispose individuals to slowly progressive fat loss, which is markedly accelerated when a PI and NRTIs are combined. Of the NRTIs, stavudine leads to an earlier onset of clinically apparent fat wasting compared with zidovudine. Fat wasting associated with NRTI use may be a manifestation of mitochondrial toxicity, which may be exacerbated by PI use.

Absorptiometry, Photon↗

PubMed1999

Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: effect of 3-alkylpyridine ring substitution.

Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP-BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP-BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection.

Administration, Oral↗

PubMed1996

High-performance liquid chromatographic method for the determination of an HIV-1 non-nucleoside reverse transcriptase inhibitor (L-696,229) in plasma samples from animals.

A sensitive high-performance liquid chromatographic (HPLC) method was developed and validated to separate and quantitate the levels of L-696,229 (I), a novel human immunodeficiency virus type I non-nucleoside reverse transcriptase inhibitor, and its hydroxy metabolites (II and III) in plasma samples. The procedure involves the addition of a constant known quantity of internal standard to the biological specimen followed by extraction of the compounds of interest into methyl tert.-butyl ether. The organic phase is evaporated to dryness under a gentle stream of nitrogen. The residue is then dissolved in methanol and water and injected onto a reversed-phase HPLC column. A gradient HPLC method is used to elute the compounds which are monitored using UV detection at 319 nm. Absolute calibration factors (from the standard curve) were calculated by analyzing standards, and these factors were used to determine the concentration of drug (I) and its hydroxy metabolites (II and III) in the samples using the internal standard method. The method was linear using a standard concentration range of 50 to 20,000 ng/ml. The limit of quantitation was 50 ng/ml using 200 microliters plasma. The procedure was utilized to monitor plasma levels of I, II and III in acute and chronic toxicity studies in several animal species.

Animals↗

PubMed2005

Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives.

In this paper we describe our structure-based ligand design, synthetic strategy, and structure-activity relationship (SAR) studies that led to the identification of thiocarbamates (TCs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), isosteres of phenethylthiazolylthiourea (PETT) derivatives. Assuming as a lead compound O-[2-(phthalimido)ethyl]phenylthiocarbamate 12, one of the precursors of the previously described acylthiocarbamates (Ranise, A.; et al. J. Med. Chem. 2003, 46, 768-781), two targeted solution-phase TC libraries were prepared by parallel synthesis. The lead optimization strategy led to para-substituted TCs 31, 33, 34, 39, 40, 41, 44, 45, and 50, which were active against wild-type HIV-1 in MT-4-based assays at nanomolar concentrations (EC50 range: 0.04-0.01 microM). The most potent congener 50 (EC50 = 0.01 microM) bears a methyl group at position 4 of the phthalimide moiety and a nitro group at the para position of the N-phenyl ring. Most of the TCs showed good selectivity indices, since no cytotoxic effect was detected at concentrations as high as 100 microM. TCs 31, 37, 39, 40, and 44 significantly reduced the multiplication of the Y181C mutant, but they were inactive against K103R and K103N + Y181C mutants. Nevertheless, the fold increase in resistance of 41 was not greater than that of efavirenz against the K103R mutant in enzyme assays. The docking model predictions were consistent with in vitro biological assays of the anti-HIV-1 activity of the TCs and related compounds synthesized.

Anti-HIV Agents↗

PubMed2000

Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives.

Through computationally directed broad screening, a novel 1, 5-diphenylpyrazole (DPP) class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been discovered. Compound 2 (PNU-32945) was found to have good activity versus wild-type (IC(50) = 2.3 microM) and delavirdine-resistant P236L (IC(50) = 1.1 microM) reverse transcriptase (RT). Also, PNU-32945 has an ED(50) for inhibition of viral replication in cell cultures of 0.1 microM and was shown to be noncytotoxic with a CC(50) > 10 microM. Structure-activity relationship studies on the 3- and 4-positions of PNU-32945 led to interesting selectivity and activity within the class. In particular, the 3-hydroxyethyl-4-ethyl congener 29 is a potent inhibitor of the P236L mutant (IC(50) = 0.65 microM), whereas it is essentially inactive versus the wild-type enzyme (IC(50) > 50 microM). Furthermore, this compound was significantly more active versus the P236L mutant than delavirdine. The synthesis and RT inhibitory activity of various 3- and 4-substituted analogues are discussed.

Anti-HIV Agents↗

PubMed2002

Performance of an in-house genotypic antiretroviral resistance assay in patients pretreated with multiple human immunodeficiency virus type 1 protease and reverse transcriptase inhibitors.

An in-house genotypic antiretroviral resistance assay was evaluated by testing 32 plasma samples obtained from heavily pretreated human immunodeficiency virus type 1 (HIV-1)-infected patients failing multiple antiretroviral regimens. The same samples were also sent to Virco Laboratories for genotypic (VircoGEN) and phenotypic (Antivirogram) resistance analysis. Sequencing results obtained by in-house (HG) and VircoGEN (VG) genotyping were concordant for 387 of 400 (96.75%) drug resistance mutations. Genotype-based prediction of drug susceptibility for 13 currently licensed antiretroviral compounds were in agreement in 336 (80.78%) cases, partially concordant in 73 (17.54%) cases and discordant in only seven (1.68%) cases. VG indicated 'possible resistance' twice as much as HG. When genotype interpretation was compared with the Antivirogram phenotypic data, there were 27 (6.49%) and 23 (5.52%) wrong calls by HG and by VG, respectively. Both assays were more sensitive in detecting drug resistance than drug susceptibility (94.61 vs. 65.19% for HG, 80.84 vs. 56.91% for VG) and more specific in detecting drug susceptibility than drug resistance (93.62 vs. 73.49% for HG, 93.62 vs. 80.32% for VG). Rule-based algorithms can reliably interpret genotypic data obtained from most heavily pretreated patients. However, occasional genotypic patterns may be erroneously interpreted without resistance phenotyping.

Anti-HIV Agents↗

PubMed2002

Body composition changes in protease inhibitor-naive HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors.

OBJECTIVES: In the era of highly active antiretroviral treatment (HAART), there are insufficient data regarding lipodystrophy syndromes in HIV-1-infected patients treated with regimens that do not include protease inhibitors (PIs). We studied changes in body composition in HIV-1-infected patients before and 2 years after starting a non-PI-containing antiretroviral treatment regimen. METHODS: We studied retrospectively the whole body dual energy X-ray absorptiometry (DEXA) scans of 23 PI-naive HIV-1-infected patients (17 males, six females), aged 37.4 +/- 9.3 years with mean CD4 count 401 +/- 130 cells/microL. Thirteen patients were on zidovudine (ZDV) + lamivudine (3TC) and 10 on ZDV + didanosine (ddI). Subjects were evaluated before the beginning of antiretroviral treatment and approximately 24 months later. For each patient body weight, CD4 T-cell counts, bone mineral content (BMC), bone mineral density (BMD) and whole body as well as regional fat and lean body mass were evaluated. RESULTS: A significant decrease in BMC was observed, although the T scores remained within the normal limits. Our patients also exhibited a significant decrease in body weight due almost exclusively to fat loss, while lean mass was minimally affected. Fat loss was statistically significant in the arms and legs, but not in the trunk. The above changes were most prominent in the ZDV + 3TC treatment group; in this group of patients, fat loss was also evident in the trunk. Patients on ZDV + ddI, on the other hand, only showed a significant increase in their legs' lean mass; they preserved their total fat mass and exhibited no other significant changes between the two assessments. CONCLUSIONS: Dual NRTI therapy contributes to fat loss and reduction of bone mineral content in otherwise healthy, clinically stable, PI-naive HIV-infected adults. Compared with patients on ZDV + ddI, patients on ZDV + 3TC had a more prominent fat loss in all body regions.

Absorptiometry, Photon↗

PubMed2003

Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation.

OBJECTIVE: The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research. DESIGN: A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model. METHODS: Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes. RESULTS: In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity. CONCLUSIONS: Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

Acrylic Resins↗

PubMed2001

Indinavir did not increase the short-term risk of adverse cardiovascular events relative to nucleoside reverse transcriptase inhibitor therapy in four phase III clinical trials.

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

Anti-HIV Agents↗

PubMed1996

Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain.

A human immunodeficiency virus type 1 (HIV-1)-seropositive patient was treated sequentially with the dideoxynucleoside (ddN) analogues zidovudine, didanosine, zalcitabine, stavudine, and lamivudine and the nonnucleoside HIV-1-specific reverse transcriptase inhibitor (NNRTI) loviride (alpha-APA). Accumulation of drug resistance mutations (mainly V75I, F77L, K103N, F116Y, Q151M, and M184V) eventually resulted in a strain that was genotypically and phenotypically resistant to all tested ddNs and the majority of NNRTIs. However, the multidrug-resistant virus retained wild type sensitivities to drugs such as foscarnet, phosphonomethoxyethyl adenine, dextran sulfate, JM3100, saquinavir, and NNRTI TSAO-m3T. Drug-resistant isolates showed replication kinetics and infectivity in an in vitro peripheral blood mononuclear cell system similar to those of the wild type isolate from the same patient. The multi-ddN-resistant isolate was not eliminated in a competition culture with the wild type isolate. Sequential therapy did not prevent the appearance of multidrug-resistant virus with a conserved replication rate.

Antiviral Agents↗

PubMed2004

The role of nucleoside reverse transcriptase inhibitors in the fat redistribution syndrome.

Fat redistribution associated with the use of antiretroviral therapy, which has been broadly termed 'lipodystrophy', incorporates distinct body composition changes including lipoatrophy (subcutaneous fat loss) as well as fat accumulation. This review examines the role of nucleoside reverse transcriptase inhibitor (NRTI) therapy in the overall context of lipodystrophy, providing converging evidence from observational cohort studies, clinical trials and pathological studies that lipoatrophy is strongly and specifically associated with the use of certain NRTI drugs (stavudine more than zidovudine), and that host factors also have a modulating effect on risk of NRTI-associated lipoatrophy. Implications for clinical assessment and management are also considered, within a broader contest that incorporates treatment efficacy as well as toxicity.

Antiretroviral Therapy, Highly Active↗

PubMed1995

Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high-level resistance to L-697,661, a nonnucleoside reverse transcriptase inhibitor.

L-697,661 is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase (RT) inhibitor. Its tolerability and activity in combination with zidovudine were evaluated in a 48-week double-blind study. One hundred nineteen zidovudine-naive HIV-1-infected patients with CD4 cell counts of 200-500/mm3 received either combination therapy, L-697,661 alone, or zidovudine alone. Activity was assessed by CD4 cell count changes. Selection for L-697,661-resistant virus was monitored by susceptibility testing of RT expressed by circulating viral RNA. Therapy was generally well tolerated. All groups receiving zidovudine exhibited transient increases in CD4 cell counts, while the L-697,661 monotherapy group showed a significant decline and yielded RT > 100-fold resistant to L-697,661 and associated with substitutions at RT residue 181. The RT from patients receiving combination therapy was maximally 15-fold less susceptible to L-697,661. Hence, cotreatment with zidovudine prevents selection of HIV-1 variants that are highly resistant to L-697,661 in patients naive to both compounds.

Adult↗

PubMed1988

Persistence of human immunodeficiency virus antigenemia in patients with the acquired immunodeficiency syndrome treated with a reverse transcriptase inhibitor, suramin. Ten-patient case-control study.

Ten homosexual men with the acquired immunodeficiency syndrome were included in a serologic follow-up study (duration, 40 weeks) of human immunodeficiency virus (HIV) antigenemia. Five of these men were treated with the reverse transcriptase inhibitor, suramin, for a period of 19 to 37 weeks. In contrast with reported changes in HIV antigen levels after treatment with zidovudine, HIV antigenemia persisted in the suramin-treated group, as well as in the untreated group. No clinical or immunologic improvement was seen in either group within the observation period. These data add evidence to the notion that monitoring HIV antigen levels helps to assess the efficacy of antiviral therapy.

Acquired Immunodeficiency Syndrome↗

PubMed2001

3,3a-Dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones are potent non-nucleoside reverse transcriptase inhibitors.

A series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione were found to be HIV-1 non-nucleoside reverse transcriptase inhibitors. One of these compounds, as the racemate, possessed an IC90 = 4.6 nM against wild-type virus in a whole cell antiviral assay and had an IC90 = 76 and 897 nM against the clinically significant K103N and K103N/L100I mutant viruses, respectively.

Binding Sites↗

PubMed2005

Initiation of antiretroviral treatment with dual nucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected infants with less advanced disease in a resource-limited setting: a multi-center study in Thailand 1998-2000.

OBJECTIVES: To evaluate the feasibility, duration of efficacy, and outcome of therapy with dual nucleoside reverse transcriptase inhibitors (NTRI) initiated in HIV-infected infants with mild to moderate disease. MATERIAL AND METHOD: During 1998-2000, a multi-center prospective open-labeled operational study was conducted. Antiretroviral naôve HIV-infected infants were enrolled in seven hospitals to receive either zidovudine (AZT) plus lamivudine (3TC) or AZT plus didanosine (ddI). Infants who were in CDC stage "C3" were excluded from the study. RESULTS: Of the 88 infants, the mean age of treatment initiation was 6.8 months, and the mean initial CD4 was 1538 cells/mm3 (21.4%). The z-scores for weight and height increased after 4-8 months of treatment, and by the 24th month, were +0.89 and +0.69 higher than at enrollment. The CD4% peak increased at 8 months of treatment, by a mean increment of 4.19%, but decreased to the level of 1.08% above baseline by the 24th month of treatment. Three (3.4%) infants died, 11 (12%) had disease progression, 7 (8%) was prematurely discontinued from the study protocol due to poor compliance, and 37 (42%) were lost to follow-up. At the end of 24 months, all remaining 30 children were in stable condition with a chance of clinical and immunological stability of 34% and 68% by intention-to-treat and on-treatment analysis, respectively. CONCLUSION: Clinical and immunological benefit from dual NRTI was limited. Treatment of HIV-infected infant with mild to moderate disease in a resource-limited setting may have limited feasibility due to the high drop-out rate.

Developing Countries↗

PubMed2005

Aminopyrimidinimino isatin analogues: design of novel non- nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum chemotherapeutic properties.

PURPOSE: HIV is the most significant risk factor for many opportunistic infections such as tuberculosis, hepatitis, bacterial infections and others. In this paper, we describe an aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related opportunistic infections. METHODS: The synthesis of various aminopyrimidinimino isatin derivatives was achieved in two steps and evaluated for anti-HIV, anti-HCV, antimycobacterial and antibacterial activities. RESULTS: Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7[[N4-[3'-(4'-amino-5'-trimethoxybenzylpyrimidin-2'-yl)imino-1'-isatinyl] methyl]N1-piperazinyl]-3-quinoline carboxylic acid (14) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, M. tuberculosis and various pathogenic bacteria. Among the synthesized compounds compound 14 and 15 emerged as more promising broad-spectrum chemotherapeutic agents.

Aminopyridines↗

PubMed1994

Is there a role for non-nucleoside reverse transcriptase inhibitors in the treatment of HIV infection?

Because the efficacy of currently approved antiretroviral agents used as prolonged monotherapy is limited, there is an urgent need for alternative agents for the treatment of HIV infection. We review the development of a diverse group of new compounds, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are potent and specific inhibitors of HIV replication. Early clinical experience with the NNRTIs has demonstrated antiviral activity and a high therapeutic index, but some patients rapidly develop viral strains resistant to these drugs. The contributions of NNRTI studies to the basic science of HIV pathogenesis and the potential clinical role of these compounds, particularly in combination antiretroviral regimens, are discussed.

Antiviral Agents↗

PubMed2004

Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1.

Almost fifteen years ago, the first non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) lead compounds have been discovered. Nowadays, three NNRTIs are approved for treatment of HIV-1-infected individuals and several others are subject of (advanced) clinical trials. Although the NNRTIs target HIV-1 RT, they are clearly different from the nucleoside RT inhibitors (NRTIs). They are highly selective for HIV-1 and do not inhibit HIV-2 or any other (retro)virus. They target HIV-1 RT by a direct interaction without the need to be metabolised by cellular enzymes, and they interact at a site on the HIV-1 RT that is near to, but distant from, the substrate-binding site. The majority of NNRTIs share common conformational properties and structural features that let them fit in a hydrophobic pocket at the HIV-1 RT, which is nowadays well-characterized. A wide variety of crystal structures of RT complexed with NNRTIs have been obtained. They provide detailed insights in the molecular interaction of the NNRTIs with the amino acids lining the pocket in HIV-1 RT. Due to their unprecedented specificity, the NNRTIs are relatively non-toxic in cell culture, and the most potent compounds reach selectivity indices that exceed 100,000 or more. However, inherent to their high specificity, the NNRTIs easily select for mutant virus strains with several degrees of drug resistance. The first-generation NNRTIs such as nevirapine and delavirdine easily loose their inhibitory potential against mutant virus strains that contain single amino acid mutations in their RT. The second-generation NNRTIs such as efavirenz, capravirine and etravirine [corrected] usually require two or more mutations in the HIV-1 RT before significantly decreasing their antiviral potency. Evidently, it requires a markedly longer time period to obtain significant resistance against second-generation NNRTIs. The resistance spectrum of NNRTIs is entirely different from the NRTI resistance spectrum, and, as a rule, NRTI-resistant mutant virus strains keep full sensitivity to the inhibitory effects of NNRTIs, and vice versa NNRTI-resistant and mutant virus strains keep full sensitivity to the inhibitory effects of NRTIs. NNRTIs have proven beneficial when included in drug combination (triple or quadruple) therapy, preferably in the presence of protease inhibitors and NRTIs.

Anti-HIV Agents↗