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PubMed2000

Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors.

A previously published report provided guidelines for managing the pharmacologic interactions that can result when patients receive protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection together with rifamycins for the treatment of tuberculosis (TB). Protease inhibitors and NNRTIs are antiretroviral agents that are substrates that may inhibit or induce cytochrome P-450 isoenzymes (CYP450). Rifamycins are antituberculosis agents that induce CYP450 and may decrease substantially blood levels of the antiretroviral drugs. The pharmacologic interactions are called "drug-drug" because, in addition to the effect rifamycins have on protease inhibitors and NNRTIs, the antiretroviral agents may affect the blood levels of rifamycins. This notice presents updated data pertaining to drug-drug interactions between these agents and recommendations for their use from a group of CDC scientists and outside expert consultants.

AIDS-Related Opportunistic Infections↗

PubMed2003

The effects of protease inhibitors and nonnucleoside reverse transcriptase inhibitors on p-glycoprotein expression in peripheral blood mononuclear cells in vitro.

Several antiretroviral compounds have been shown to be substrates for the efflux protein P-glycoprotein (P-gp) although few studies have investigated the effects of drug on expression of this protein. Here, an in vitro system has been adopted to investigate the effects of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) on P-gp expression in peripheral blood mononuclear cells (PBMCs). PBMCs isolated from healthy volunteers were incubated with 10 or 100 microM PI (saquinavir, ritonavir, lopinavir, indinavir, nelfinavir, amprenavir) or 10 microM NNRTI (efavirenz, nevirapine) for 72 hours. Surface P-gp expression was measured by flow cytometry and compared with vehicle-incubated controls. Toxicity was assessed by MTT assay and the effects of each compound were compared between individuals with differing genotypes at position 3435 of exon 26 of MDR1, which was assigned by restriction fragment length polymorphism. Significant increases in median P-gp expression were observed following incubation with 10 microM nelfinavir (10.2 versus 6.7% P-gp-positive cells) and efavirenz (10.0 versus 6.7% P-gp-positive cells). No significant differences in induction were observed between genotypes (CC, CT, TT). Following incubation with 100 microM PI, significant upregulation of P-gp occurred except with amprenavir. However, nelfinavir, ritonavir, and lopinavir caused marked toxicity, indicating that at higher concentrations, the increase in P-gp may be at least partially related to a stress response. These results indicate the potential of some PIs and NNRTIs to induce P-gp expression in PBMCs in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Synthesis and biological evaluation of prodrug-type anti-HIV agents: ester conjugates of carboxylic acid-containing dipeptide HIV protease inhibitors and a reverse transcriptase inhibitor.

On the basis of substrate transition-state mimic concept of HIV protease, a series of small-sized dipeptide inhibitors containing hydrophilic carboxyl group were designed and synthesized. These dipeptide inhibitors showed good HIV protease inhibitory activity, but their anti-HIV activity was poor. The low antiviral activities of these inhibitors were probably due to their inadequate cell membrane permeability caused by the presence of a free carboxylic acid in the inhibitors. Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, conjugates of HIV protease inhibitors with a nucleoside reverse transcriptase inhibitor were synthesized. Some of these conjugates exhibited excellent antiviral activity compared with that of individual inhibitors. The synergistic enhancement of anti-HIV activities of these conjugates may be due to their ability to penetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agents in the cytoplasm.

Animals↗

PubMed2004

Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors are potent, highly specific, noncompetitive inhibitors of the Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. They are used commonly as part of potent antiretroviral regimens for the treatment of HIV-1 infection, either in combination with nucleoside analogs, protease inhibitors, or both. A major limitation to the success of non-nucleoside inhibitors is the rapid emergence of HIV-1 variants resistant to these drugs. These drug-resistant variants contain one or more mutations in the non-nucleoside inhibitor binding pocket of reverse transcriptase. This review summarizes the effects that these mutations have on non-nucleoside inhibitor binding, reverse transcriptase structure, HIV-1 replication, and the ability of reverse transcriptase to catalyze DNA polymerization and RNase H cleavage. In addition, studies are summarized evaluating important interactions between mutations conferring resistance to non-nucleoside inhibitors and those conferring resistance to nucleoside analogs. The studies summarized in this review provide important insights into potentially useful approaches to minimize the development of HIV-1 resistant to non-nucleoside inhibitors.

Codon↗

PubMed2002

Chimeric human immunodeficiency virus type 1 and feline immunodeficiency virus reverse transcriptases: role of the subunits in resistance/sensitivity to non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are specific for human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and do not inhibit HIV-2. Given that the amino acids lining the NNRTI-specific pocket of HIV-1 RT display higher similarity to the corresponding feline immunodeficiency virus (FIV) RT amino acids than to HIV-2 RT, the susceptibility of FIV RT and chimeric HIV-1/FIV RTs to NNRTIs and the role of the p51 subunit in the inhibitory action of NNRTIs were investigated. We found that the wild-type FIV RT and the FIVp66/HIVp51 chimeric enzyme showed no susceptibility for NNRTIs. On the other hand, the chimeric HIVp66/FIVp51 RT retained a sensitivity spectrum for NNRTIs similar to that of the wild-type HIV-1 RT. The noncompetitive nature of inhibition of HIV-1 RT by nevirapine was also observed with the HIVp66/FIVp51 chimeric enzyme. Inhibition of the chimeric RTs by nucleoside reverse transcriptase inhibitors and foscarnet was in the same range as observed for the corresponding HIVp66/HIVp51 and FIVp66/FIVp51 wild-type enzymes. The chimeric RTs had an affinity (K(m)) for their dNTP substrate and template/primer comparable with that of the wild-type HIV-1 and FIV RTs, but their catalytic efficacy (k(cat)) was markedly decreased. This decreased catalytic efficacy of the RT chimeras may suggest suboptimal interactions between p66 and p51 in the chimeric enzymes. Our results point to a minor role of the p51 subunit in the sensitivity to RT inhibitors.

Amino Acid Sequence↗

PubMed2005

Altered adipokine response in murine 3T3-F442A adipocytes treated with protease inhibitors and nucleoside reverse transcriptase inhibitors.

BACKGROUND: Abnormal levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and adiponectin have been observed in HIV patients with lipodystrophy. However, because these patients have long drug and disease histories, it is unclear which drugs are responsible for these abnormalities. We have therefore investigated the effects of individual antiretrovirals on adipokine expression and adipogenesis using a murine cell line in vitro. METHODS: Differentiating murine 3T3-F442A adipocytes were incubated with 20 microM nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine or stavudine, or protease inhibitors (PIs) indinavir, ritonavir, saquinavir or nelfinavir, in the presence and absence of rosiglitazone (10 microM). Adipogenesis was assessed using glycerol-3-phosphate dehydrogenase activity, while expression of TNF-alpha, IL-6 and adiponectin at protein and mRNA levels was assessed by ELISA and quantitative real-time PCR, respectively. RESULTS: Nelfinavir, ritonavir and saquinavir inhibited adipogenesis and up-regulated the expression of TNF-alpha and IL-6, but this effect was not seen with indinavir, zidovudine and stavudine. Adiponectin expression was significantly reduced in both NRTI- and PI-treated cells, although the most profound reductions were found with ritonavir and saquinavir. Co-incubation with rosiglitazone led to a partial attenuation of the change in TNF-alpha, IL-6 and adiponectin secretion. CONCLUSIONS: Our data suggest that the PIs nelfinavir, ritonavir and saquinavir have potent effects in inhibiting adipocyte differentiation whilst up-regulating TNF-alpha and IL-6 mRNA levels and decreasing adiponectin levels. These changes were partially attenuated by rosiglitazone. Taken together, the data show that antiretrovirals have complex effects on adipocyte function, which may be mediated by an altered adipokine response.

3T3 Cells↗

PubMed1994

The genetic and functional basis of HIV-1 resistance to nonnucleoside reverse transcriptase inhibitors.

The nonnucleoside reverse transcriptase (RT) inhibitors are structurally diverse compounds that are specific inhibitors of the human immunodeficiency virus type 1 RT enzyme. The compounds are largely functionally identical and bind to a common site in the enzyme. HIV-1 variants that exhibit reduced susceptibility to these inhibitors have been derived in cell culture and, more recently, from HIV-1-infected patients undergoing experimental therapy. The variants express amino acid substitutions at RT positions that apparently interact directly with the inhibitors. Effects of specific substitutions at these positions vary among the compounds, suggesting subtle differences in how the compounds physically interact with the enzyme.

Antiviral Agents↗

PubMed2001

Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that induce allosteric changes in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, thus rendering the enzyme incapable of converting viral RNA to DNA. Unlike nucleoside analogue inhibitors of reverse transcriptase, NNRTIs do not require sequential phosphorylation to elicit antiretroviral activity. There are currently 3 approved NNRTIs: nevirapine, delavirdine and efavirenz. Although possessing a common mechanism of action, these agents can be differentiated by both molecular and pharmacokinetic characteristics. Each of the NNRTIs is metabolised to some degree by the cytochrome P450 (CYP) system of enzymes, making them prone to clinically significant drug interactions. In addition, they elicit variable effects on other medications, acting as either inducers or inhibitors of drugs metabolised by CYP. These drug interactions are an important consideration in the clinical use of these agents as a part of combination antiretroviral therapy. Additional factors such as the influence of food and pH on oral absorption, and protein binding, must also be considered.

Alkynes↗

PubMed1996

Kinetic analysis of intravirion reverse transcription in the blood plasma of human immunodeficiency virus type 1-infected individuals: direct assessment of resistance to reverse transcriptase inhibitors in vivo.

Intravirion reverse transcripts have been identified in the blood plasma of human immunodeficiency virus type 1 (HIV-1)-infected individuals. In the present studies, the kinetic processes of intravirion HIV-1 reverse transcription, in the blood plasma of HIV-1-infected persons treated with nevirapine, were investigated. Nevirapine is a nonnucleoside inhibitor of reverse transcriptase (RT) which decreases the level of HIV-1 viral particles in the blood plasma of infected individuals. By analyzing HIV-1 virions at different time points prior to and after initiation of nevirapine therapy in vivo, the levels of intravirion reverse transcripts have been demonstrated to be dramatically susceptible to this anti-RT agent, out of proportion to effects on plasma virion load. The intravirion reverse transcripts were also documented to rebound to the pretreatment levels, concomitant with the development of resistant viral mutants. In addition, the infectivity of HIV-1 virions dramatically decreased after nevirapine treatment, further indicating that the effects of this anti-RT agent begin within the cell-free virions. Since the levels of intravirion reverse transcripts were altered according to the susceptibility or resistance of the HIV-1 RT enzyme to this inhibitor, these data demonstrate that the formation of intravirion reverse transcripts is a dynamic process in vivo. Moreover, because the alteration in ratios between intravirion HIV-1 reverse transcripts and viral genomic RNA directly reflects the efficiency of reverse transcription, we propose that the determination of these ratios in the blood plasma of HIV-1-positive patients may be a useful and, most importantly, a direct assay to monitor the efficacy of anti-RT agents in vivo.

Base Sequence↗

PubMed2005

Pharmacokinetic drug interactions with non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a diverse group of compounds that inhibit HIV Type 1 reverse transcriptase. Although possessing a common mechanism of action, the approved NNRTIs, delavirdine, efavirenz and nevirapine, differ in structural and pharmacokinetic characteristics. Each of the NNRTIs undergoes biotransformation by the cytochrome P450 (CYP) enzyme system, thus making them prone to clinically significant drug interactions when combined with other antiretrovirals. In addition, they interact with other concurrent medications and complementary/alternative medicines, acting as either inducers or inhibitors of drug-metabolising CYP enzymes. These drug interactions become an important consideration in the clinical use of these agents when designing combination regimens, as recommended by current guidelines. This review provides an updated summary of pharmacokinetic interactions with NNRTIs.

Animals↗

PubMed2003

Hologram quantitative structure-activity relationships investigations of non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT and dipyridodiazepinone are effective against HIV-1 RT. These NNRTIs are chemically and structurally diverse, but they all bind to a common allosteric site of HIV-1 RT. These inhibitors exhibit high potency, low cytotoxicity and produce few side effects. However, the emergency of drug-resistance viral strain has limited the therapeutic efficiency of the NNRTIs. Several different QSAR studies were reported to identify important structural features responsible for the inhibitory activity of these NNRTIs. In this study, hologram quantitative structure-activity relationships (HQSAR) was applied to three different data sets, 70 TIBO, 101 HEPT and 125 dipyridodiazepinone derivatives. Starting geometries of compounds were taken from available X-ray crystallographic data. Modification and full geometry optimization of all derivatives were performed, based on quantum chemical calculations at the HF/3-21G level of theory. All derived HQSAR models produce satisfying predictive ability and yield r(2)(cv) values ranging from 0.62-0.84. Moreover, it was also found that the quality of models enhances as the size of fragments increases. The obtained HQSAR results indicate the similarity of the interactions of these three different NNRTIs with the inhibition pocket of the enzyme. Comparisons of different QSAR methods on these NNRTIs data sets were also considered and it could be shown that HQSAR results yield superior predictive models than other 2D-QSAR approaches. In particular, the predictive ability of the models derived from dipyridodiazepinone analogues was significantly improved and apparently revealed differentiating structural requirements between WT and Y181C HIV RT inhibition. Additionally, the quality of QSAR models constructed by CoMFA and HQSAR methods are comparable and the interpretations of the models reinforce each other. It suggests an advantage of HQSAR as a useful tool in designing new potent inhibitors with enhanced HIV-1 RT inhibition activity, especially against mutant enzyme.

Anti-HIV Agents↗

PubMed2000

'Double-Drugs'--a new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker.

We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-drug' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components.

Anti-HIV Agents↗

PubMed2000

Isolation and characterization of simian immunodeficiency virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) act quite specifically on human immunodeficiency virus type 1 (HIV-1). In general, they are not effective on human immunodeficiency virus type 2 (HIV-2) or simian immunodeficiency virus (SIV). Only SIV strains from African green monkeys are sensitive to several NNRTIs. Here we isolated NNRTI- and 3TC-resistant SIVagm variants. Viruses resistant to delavirdine contained V112I and M231I substitutions, while those resistant to 3TC contained a M 185I substitution. These amino acids are highly conserved in HIV-1, HIV-2, SIVmac and SIVagm, and the M184I (M185I in SIVagm) substitution was observed in 3TC-resistant HIV-1 and SIVmac. The roles of the observed mutations in NNRTI-resistance of SIVagm and HIV-1 were further confirmed by site-directed mutagenesis. The present results have provided a new insight into the common mechanism of sensitivity of HIV- 1 and SIVagm to NNRTIs.

Amino Acid Sequence↗

PubMed2001

A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are selective for human immunodeficiency virus type 1 (HIV-1) and generally not effective on HIV-2 or simian immunodeficiency virus (SIV). Only SIVagm was found to be sensitive to NNRTIs. When the amino acid differences in RT between SIVmac and SIVagm were compared with the known amino acid substitutions of NNRTI-resistance variants of HIV-1, we came to consider that the amino acid residue Leu-188 of HIV-2 and SIVmac might be related to their resistance to NNRTIs. To test this hypothesis, we substituted Leu-188 to Cys or Tyr in HIV-2 and SIVmac, and examined sensitivity of the mutant molecular clones to NNRTIs. The L188Y mutant of HIV-2 became completely sensitive to delavirdine and efavirenz, while that of SIVmac was also significantly sensitive to these NNRTIs. We further isolated NNRTI-resistant variants from these mutant viruses and determined amino acid substitutions in RT. The roles of the observed substitutions in NNRTI-resistance were further confirmed by site-directed mutagenesis. Our study reveals the crucial role of L188 in the natural resistance of HIV-2 and SIVmac to NNRTIs. Furthermore, the observed substitutions in RT of HIV-2 and SIVmac support the common mechanism of action of NNRTIs against HIV-1, HIV-2 and SIV.

Alkynes↗

PubMed2001

HIV-1 reverse transcriptase mutations found in a drug-experienced patient confer reduced susceptibility to multiple nucleoside reverse transcriptase inhibitors.

HIV-1 reverse transcriptase (RT) genotypes were obtained from 13 patients treated with stavudine. No previously-reported mutations indicative of stavudine resistance were found in these patients and no novel mutations occurred in more than two patients. One patient, treated with stavudine for 1 month and treated previously with zidovudine, zalcitabine and lamivudine, carried a mutation at codon 75 of the RT (V75M). A chimeric virus, including the patient's RT sequence from codon 25 to codon 220, which carried the resistance mutations M41 L, D67N, T69D, K70R, L210W and T215Y in addition to V75M, displayed reduced susceptibility to multiple nucleoside RT inhibitors (NRTIs). Removal of V75M from this RT background resulted in a return of susceptibility to didanosine and lamivudine. Our data are in agreement with previous studies demonstrating the rarity of stavudine resistance mutations in stavudine-treated patients. However, we describe a new set of mutations, found in the RT of a heavily-treated patient, that can confer reduced susceptibility to multiple NRTIs. These results underscore the importance of increased vigilance for possible multiple-drug resistance in patients who have been heavily treated with NRTIs.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Paclitaxel in the treatment of human immunodeficiency virus 1-associated Kaposi's sarcoma--drug-drug interactions with protease inhibitors and a nonnucleoside reverse transcriptase inhibitor: a case report study.

PURPOSE: To describe the pharmacokinetics of paclitaxel and to investigate the interaction potential with protease inhibitors (indinavir, ritonavir, saquinavir) and the nonnucleoside reverse transcriptase inhibitor nevirapine, for which strong theoretical indications for clinically relevant drug interactions exist. METHODS: The 24-h plasma pharmacokinetics of paclitaxel (Taxol, given at 100 mg/m2 by 3-h intravenous infusion) and concomitantly infused antiretroviral drugs were determined in a human immunodeficiency virus 1 (HIV-1)-infected male patient with refractory Kaposi's sarcoma (KS) during high-activity antiretroviral therapy and after discontinuation of this regimen. The plasma pharmacokinetics of paclitaxel, indinavir, ritonavir, saquinavir, and nevirapine were closely monitored. Since all these drugs are extensively metabolized via the cytochrome P450 enzyme system and are substrates for the multidrug transporter P-glycoprotein, investigation of drug-drug interactions was considered important. RESULTS: In this case report study the pharmacokinetics of paclitaxel given concomitantly with various antiretroviral drugs were comparable with those of historical controls who had been treated with single-agent paclitaxel. The pharmacokinetics of indinavir, ritonavir, saquinavir, and nevirapine were also not statistically significantly different from those recorded for historical controls. Paclitaxel was well tolerated and resulted in a significant clinical response in this patient. CONCLUSION: Dose adjustments of paclitaxel, indinavir, ritonavir, saquinavir, or nevirapine are apparently not needed if HIV-1-associated KS is treated with paclitaxel at a dose of 100 mg/m2 as shown in the present case. It is stressed, however, that controlled studies are necessary to substantiate these preliminary case report findings.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Novel lavendamycin analogues as potent HIV-reverse transcriptase inhibitors: synthesis and evaluation of anti-reverse transcriptase activity of amide and ester analogues of lavendamycin.

Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformations of 13-15 and 17. Several lavendamycins were found to be potent HIV reverse transcriptase inhibitors with very low toxicity in vitro and in vivo. Several compounds also acted either additively or synergistically to inhibit enzyme activity together with AZT-triphosphate.

Amides↗

PubMed2002

Simultaneous quantitative assay of six HIV protease inhibitors, one metabolite, and two non-nucleoside reverse transcriptase inhibitors in human plasma by isocratic reversed-phase liquid chromatography.

A rapid (less than 30 min), sensitive, and specific liquid chromatography method for simultaneous assay of nine antiretroviral drugs in human plasma is described. This technique allows therapeutic drug monitoring of six approved protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and two approved non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). Assays were performed after diethyl ether liquid-liquid extraction from 250-microL plasma samples. Chromatographic separation was achieved on an X-TERRA (Waters; Saint Quentin, France) column using a 58% water (with 3 mmol/L pyrrolidine) and 42% acetonitrile mobile phase. Three ultraviolet wavelengths were used for detection with a diode array detector. This method allowed quantitative assay of all nine antiretroviral drugs within a concentration range of 25 ng/mL to 9000 ng/mL. The method has been validated extensively and has been in routine use in our laboratory for several months for drug monitoring in plasma samples from patients treated with antiretroviral drugs.

Chromatography, High Pressure Liquid↗