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PubMed1995

Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is the major target for antiretroviral therapy of the acquired immunodeficiency syndrome (AIDS). While some inhibitors exhibit activity against most retroviral RTs, others are specific for the HIV-1 enzyme. To develop an animal model for the therapy of the HIV-1 infection with RT inhibitors, the RT of the simian immunodeficiency virus (SIV) was replaced by the RT of HIV-1. Macaques infected with this SIV/HIV-1 hybrid virus developed AIDS-like symptoms and pathology. The HIV-1-specific RT inhibitor LY300046.HCl, but not zidovudine [3'-azido-3'-deoxythymidine (AZT)] delayed the appearance of plasma antigenemia in macaques infected with a high dose of the chimeric virus. Infection of macaques with the chimeric virus seems to be a valuable model to study the in vivo efficacy of new RT inhibitors, the emergence and reversal of drug resistance, the therapy of infections with drug-resistant viruses, and the efficacy of combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride.

Human immunodeficiency virus type 1 (HIV-1) strains resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may easily be selected for in vitro and in vivo under a suboptimal therapy regimen. Although cross-resistance is extensive within this class of compounds, newer NNRTIs were reported to retain activity against laboratory strains containing defined resistance-associated mutations. We have characterized HIV-1 resistance to loviride and the extent of cross-resistance to nevirapine, delavirdine, efavirenz, HBY-097, and tivirapine in a set of 24 clinical samples from patients treated with long-term loviride monotherapy by using a recombinant virus assay. Genotypic changes associated with resistance were analyzed by population sequencing. Overall, phenotypic resistance to loviride ranged from 0.04 to 3.47 log10-fold. Resistance was observed in samples from patients who had discontinued loviride for up to 27 months. Cross-resistance to the other compounds was extensive; however, fold resistance to efavirenz was significantly lower than fold resistance to nevirapine. No genotypic changes were detected in three samples; these were sensitive to all of the NNRTIs tested. The most common genotypic change was the K103N substitution. The range of phenotypic resistance in samples containing the K103N substitution could not be predicted from a genotypic analysis of known NNRTI resistance-associated mutations. The Y181C substitution was detected in one isolate which was resistant to loviride and delavirdine but sensitive to efavirenz, HBY-097, and tivirapine. Our data indicate that the available newer NNRTIs which retain activity against some HIV-1 strains selected by other compounds of this class in vitro may have compromised clinical efficacy in some patients pretreated with NNRTI.

Acetamides↗
PubMed1999

A new class of anti-HIV agents: synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor.

Conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor were synthesized, which expressed excellent antiviral activity compared with that of the individual components. The remarkable antiviral activity of the conjugated compounds may be due to their penetration into the cell and later splitting into two different classes of anti-HIV agents.

Anti-HIV Agents↗
PubMed2004

Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure.

During ZDV or d4T exposure, mutations at codons 41, 67, 70, 210, 215, and 219 can be selected and were named thymidine analogue mutations (TAMs). Some previous results suggested that different TAMs patterns could exist and that the kind of TAMs pattern could influence the virological response to some nucleoside reverse transcriptase inhibitors (NRTIs). In order to get more data about the relative prevalence of these patterns, their associations with other NRTI resistance mutations and the identification of the different stages observed during the acquisition of TAMs under treatment by NRTIs, we collected 1,098 RT sequences harbouring at least one TAM from patients failing to antiretroviral regimen. Sequences were stored in a database designed specifically to allow the retrieval of sequences that met specific criteria such as the occurrence and frequency of a particular mutation, the nature and frequency of the amino acid substitution at a given codon, and/or the rate of association between resistance mutations. Two pathways of TAMs can be identified: profile #1 (T215Y mutation linked) and profile # 2 (T215F mutation linked). The frequency of selection of profile # 1 is two times higher than profile # 2. The E44D/A + V118I complex, 69 insertions, and L74V mutation are associated to profile #1, whereas the Q151M complex and M184V mutation are associated to both profiles. As some NRTI resistance mutations were associated preferentially with profile #1, further studies are needed to explore if, the weaker efficacy observed on viruses harbouring this profile using some NRTIs, could be explained by the TAMs profile itself or the other associated NRTI resistance mutations.

Anti-HIV Agents↗
PubMed2001

Mitochondrial Toxicity Associated with Nucleoside Reverse Transcriptase Inhibitor Therapy.

Nucleoside reverse transcriptase inhibitors result in a wide range of toxic side effects. These include lactic acidosis syndrome, myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, and possibly lipodystrophy. Despite the seemingly diverse nature of these side effects, all of these toxicities may be mediated by a common pathophysiologic mechanism, namely, mitochondrial toxicity resulting from nucleoside reverse transcriptase inhibitor-induced inhibition of DNA polymerase g. This article reviews the relevant mitochondrial biology and mechanism underlying nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical manifestations of this toxicity are reviewed followed by a discussion of clinical management.

Journal Article↗
PubMed2006

Substrate-dependent inhibition or stimulation of HIV RNase H activity by non-nucleoside reverse transcriptase inhibitors (NNRTIs).

HIV reverse transcriptase (HIV-RT) contains two distinct protein domains catalyzing DNA polymerase and RNase H activities. Non-nucleoside reverse transcriptase inhibitor (NNRTI) binding to HIV-RT can affect RNase H activity. The structurally diverse NNRTIs capravirine, efavirenz, GW8248, TMC-125, and nevirapine all inhibited 5'-RNA directed HIV RNase H activity as partial inhibitors with maximal inhibition of 40-65%. Potencies of RNase H inhibition correlated with the respective potencies of DNA polymerase inhibition. Mutations in the NNRTI binding site (K103N, Y181C, Y188L, and K103N/Y181C) reduced the potency of RNase H inhibition, similar to their effects on DNA polymerase activity. The NNRTIs did not affect the activity of the isolated HIV RNase H domain. In contrast, 3'-DNA directed RNase H activity of HIV-RT was mechanistically distinct from 5'-RNA directed RNase H activity and was stimulated rather than inhibited by NNRTI binding to HIV-RT. Therefore, NNRTI binding to the polymerase domain of HIV-RT interferes with RNase H activity through a long-range effect, which is affected by the structure of the RNA:DNA hybrid substrate, but is independent of NNRTI compound structure and nucleic acid substrate sequence.

Enzyme Activation↗
PubMed2004

Conformational changes in HIV-1 reverse transcriptase induced by nonnucleoside reverse transcriptase inhibitor binding.

Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of small hydrophobic compounds with diverse structures that specifically inhibit HIV-1 reverse transcriptase (RT). NNRTIs interact with HIV-1 RT by binding to a single site on the p66 subunit of the p66/p51 heterodimeric enzyme, termed the NNRTI-binding pocket (NNRTI-BP). This binding interaction results in both short-range and long-range distortions of RT structure. In this article, we review the structural, computational and experimental evidence of the NNRTI-induced conformational changes in HIV-1 RT and relate them to the mechanism by which these compounds inhibit HIV-1 reverse transcription.

Anti-HIV Agents↗
PubMed2003

Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors.

Nucleoside reverse-transcriptase inhibitor (NRTI) therapy for human immunodeficiency virus (HIV) infection has been associated with mitochondrial DNA (mtDNA) polymerase-gamma inhibition and subsequent mtDNA depletion. Effects on mtDNA mutation, although suggested by critical involvement of polymerase-gamma in DNA-repair reactions, are unknown. In the present study, we assessed the nature and frequency of mitochondrial genome sequence differences in peripheral-blood samples taken prior to NRTI therapy and after 6-77 mo of treatment in 16 NRTI-treated patients. Samples from 10 HIV-infected, treatment-naive control individuals were taken at similar time intervals. Single-stranded conformation polymorphism (SSCP) and DNA-sequencing analysis techniques were used to detect mitochondrial genome sequence variants between paired longitudinal samples, and heteroplasmic populations were quantified after cloning and repeat SSCP/sequencing. Of 16 individuals treated with NRTIs, 5 exhibited altered SSCP profiles associated with the development of novel heteroplasmic DNA sequence changes, whereas no SSCP pattern change within these regions was observed in the control individuals. Heteroplasmic sequence changes were distributed across four regions of the genome: the noncoding region to 12S ribosomal RNA, reduced-nicotinamide-adenine-dinucleotide dehydrogenase 1, and cytochrome oxidase subunits I and III. Of the total of 26 patients who were examined in the present study, 4 of 5 patients with detectable mtDNA sequence changes since commencement of therapy developed evidence of peripheral fat wasting (lipoatrophy) between sample intervals (P=.031). One patient, without detectable sequence changes on NRTI therapy, also developed lipoatrophy. Levels of mtDNA copies/cell in blood samples were determined by quantitative PCR for 11 of the 16 NRTI-exposed patients; 7 of these 11 patients showed reduced levels of mtDNA in blood after therapy, including all 3 patients tested with evidence of mtDNA sequence changes on therapy. These data indicate that NRTI therapy provides conditions permissive for the development of peripheral-blood mtDNA mutations in vivo.

Base Sequence↗
PubMed1999

[Pharma-clinics. How I treat ... HIV infection. III. Non-nucleoside reverse transcriptase inhibitors].

Non nucleoside reverse transcriptase inhibitors (NNRTI) are a new arm in the treatment of the HIV infection. They inhibit the replication by direct non competitive binding to the enzyme, and do not require phosphorylation. The fast emergence of resistance in monotherapy obliges to use them in a triple association. The 103 mutation confers a cross-resistance. The most common adverse event is rash. Association with nucleoside analogues is additive or even synergistic. They are metabolized by the cytochrome P450. Within a combined therapy, their efficiency is comparable to protease inhibitors, notably in patients with low viral load.

Cytochrome P-450 Enzyme System↗
PubMed2000

Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs).

Nucleoside reverse transcriptase inhibitors (NRTIs), such as 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine and 2',3'-dideoxy-3'-thiacytidine, are effective inhibitors of human immunodeficiency type 1 (HIV-1) replication. NRTIs are deoxynucleoside triphosphate analogs, but lack a free 3'-hydroxyl group. Once NRTIs are incorporated into the nascent viral DNA, in reactions catalyzed by HIV-1 reverse transcriptase (RT), further viral DNA synthesis is effectively terminated. NRTIs should therefore represent the ideal antiviral agent. Unfortunately, HIV-1 inevitably develops resistance to these inhibitors, and this resistance correlates with mutations in RT. To date, three phenotypic mechanisms have been identified or proposed to account for HIV-1 RT resistance to NRTIs. These mechanisms include alterations of RT discrimination between NRTIs and the analogous dNTP (direct effects on NRTI binding and/or incorporation), alterations in RT-template/primer interactions, which may influence subsequent NRTI incorporation, and enhanced removal of the chain-terminating residue from the 3' end of the primer. These different resistance phenotypes seem to correlate with different sets of mutations in RT. This review discusses the relationship between HIV-1 drug resistance genotype and phenotype, in relation to our current knowledge of HIV-1 RT structure.

Anti-HIV Agents↗
PubMed2001

International perspectives on antiretroviral resistance. Nucleoside reverse transcriptase inhibitor resistance.

Nucleoside reverse transcriptase inhibitors (NRTIs) comprise the first class of drug with proven antiretroviral efficacy against HIV-1, and the first in which drug resistance was reported. Ongoing research in the area of NRTI resistance and cross-resistance contributes much to what we know about the failure of antiretroviral therapy. The genetic mutation patterns responsible for resistance to the available NRTIs have been well documented. This information is being used to plan rational drug therapy. Furthermore, it serves as the standard against which to evaluate response patterns to multiple-drug regimens, ultimately enabling more accurate prediction of outcome with combination therapies. Other features of NRTI resistance, such as the theoretic reversal of zidovudine resistance associated with the M184V mutation or the powerful influence of the Q151M multiple-drug resistance mutation, have revealed the unpredictable nature of HIV resistance and how much we still need to learn. Although NRTIs are the cornerstone of antiretroviral therapy at present and are used to control disease progression for extended periods, it is clear that eventually resistance occurs with all antiretroviral regimens. Future research into NRTI-resistance mutations, mutational interactions, treatment sequencing, and viral fitness and fidelity will continue to refine our understanding of drug resistance and improve our ability to delay or eliminate resistance and advance HIV control.

Dideoxynucleosides↗
PubMed2000

Analysis of env sequence evolution in human immunodeficiency virus-infected patients receiving therapy with nonnucleoside reverse-transcriptase inhibitors.

Nonnucleoside reverse-transcriptase inhibitors (NNRTIs) can rapidly select for drug-resistant human immunodeficiency virus type 1 (HIV-1) variants, although their effect on HIV-1 quasi-species diversity is unknown. To determine if changes in env gene diversification occur with NNRTI therapy, we used the heteroduplex tracking assay (HTA) to study HIV-1 env sequence diversity in 2 groups of patients: those who were on no therapy or were on chronic antiretroviral therapy and those who had just initiated NNRTIs. Forty-nine paired samples from 46 patients were analyzed. Fourteen of 32 paired samples from the NNRTI group and 9 of 17 paired samples from the control group had HTA changes (P>.10). There was no correlation between HTA change and sampling time interval, baseline virus load, change in virus load, or development of NNRTI resistance. Thus, we found no significant correlation of NNRTI therapy with changes in env HTA patterns, suggesting that these treatments had little short-term impact on HIV-1 quasi-species diversity.

Drug Resistance, Microbial↗
PubMedDate not supplied

Mild to moderate symptoms do not correlate with lactate levels in HIV-positive patients on nucleoside reverse transcriptase inhibitors.

PURPOSE: Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with mitochondrial toxicities ranging from asymptomatic hyperlactatemia to fatal lactic acidosis. It is uncertain whether mild clinical symptoms predict hyperlactatemia and the need to consider changes in antiretroviral therapy. This cross-sectional study evaluated whether an association exists between mild symptoms and lactate levels. METHOD: HIV-positive patients on NRTIs attending routine clinic visits were surveyed about symptoms associated with hyperlactatemia. Symptom severity was quantified using Likert scales, and the sum was converted into a symptom score ranging from 0 to 30. Tourniquet-free blood specimens were collected simultaneously to measure serum lactate. Symptom scores were compared between patients with normal and elevated lactates. RESULTS: 284 individuals were included. The most common NRTIs used included lamivudine (79%), zidovudine (50%), abacavir (39%), and stavudine (24%). Twenty-two patients (8%) had increased lactates (mean = 2.7 mmol/L; range, 2.1-4.5 mmol/L), while 262 patients (92%) had normal lactates (mean = 1.2 mmol/L, range, 0.1-2.0 mmol/L). Median symptom scores were similar between groups (3 vs. 2, p = .23). Spearman's correlation coefficient for lactate and symptom score was 0.07 (p = .22). CONCLUSIONS: Mild symptoms did not correlate with lactate levels, and symptoms alone should not trigger clinicians to measure serum lactates and stop NRTIs if the levels are elevated.

Abdominal Pain↗
PubMed2005

Elevated plasma concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors in patients coinfected with human immunodeficiency virus and hepatitis B or C: case series and literature review.

STUDY OBJECTIVE: To evaluate antiretroviral pharmacokinetics in patients who are coinfected with human immunodeficiency virus (HIV) and hepatitis B and/or C virus. Specifically, we sought to determine whether coinfection results in higher than expected concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). DESIGN: Case series. SETTING: Human immunodeficiency virus clinic. PATIENTS: Twenty-six patients infected with HIV and hepatitis B and/or C virus. MEASUREMENTS AND MAIN RESULTS: Patients' plasma trough concentrations (Cmeasured) of protease inhibitors and NNRTIs were compared with population average trough concentrations reported in the literature (Cpredicted). Trough concentrations were obtained irrespective of the patients' liver function. A concentration ratio of Cmeasured: Cpredicted was determined for each patient. The mean concentration ratio of the 26 patients was 1.43 (95% confidence interval 1.08-1.78). For the six patients taking nelfinavir, the ratio of nelfinavir's active metabolite (M8): parent drug was calculated. The median M8:nelfinavir ratio for these six patients was 69% lower than what has been reported in a general HIV population. CONCLUSION: These preliminary findings suggest that trough concentrations of protease inhibitors and NNRTIs may be elevated in patients with HIV infection who are coinfected with hepatitis B and/or C, compared with a general population of patients with HIV infection. Until further investigation defines the relationship between coinfection, metabolic dysfunction, and increased antiretroviral exposure, therapeutic drug monitoring may be helpful to identify coinfected patients at risk for antiretroviral toxicity secondary to elevated plasma drug concentrations.

Chromatography, High Pressure Liquid↗
PubMed2001

Design, synthesis, and biological evaluation of anti-HIV double-drugs. conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers.

Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisting of HIV protease inhibitors conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two different classes of inhibitors has been investigated. Double-drugs using a succinyl amino acid linker were shown to release the parent drugs via spontaneous imide formation at a faster rate compared to compounds using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Among the double-drugs, KNI-1039 (3b) with a glutarylglycine linker exhibited extremely potent anti-HIV activity compared with that of the individual components. Double-drug 3b was relatively stable in culture medium, whereas it regenerated active species in cell homogenate. These results suggested that the synergistic enhancement of anti-HIV activities of 3b 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↗
PubMed2006

Pharmacologic optimization of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (POPIN)--a randomized controlled trial of therapeutic drug monitoring and adherence support.

We evaluated the feasibility and effectiveness of therapeutic drug monitoring (TDM) and adherence support (collectively, AT) vs standard of care (SOC) in patients receiving HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) within a nurse-led clinic. Primary end points were failure to achieve viral load of <50 copies/mL at 24 weeks, viral rebound, or development of treatment limiting toxicity. One hundred twenty-two patients (AT 63 and SOC 59) were followed-up every 12 weeks, for a median of 72 weeks. No difference was observed between arms in risk of reaching a study end point or between groups of patients with abnormal vs "therapeutic" drug concentrations. Interindividual variabilities (coefficient of variation) were the following: efavirenz, 77.5%; nevirapine, 74.5%; lopinavir, 73.4%; nelfinavir, 83.7%; indinavir, 80.8%; saquinavir, 112.4%. Intraindividual variabilities (median coefficient of variation) were the following: NNRTIs, approximately 25%; PIs, 48.4%. Despite persistently abnormal results in 26 of patients in the AT arm (38%), dosage adjustment was only undertaken in 9 patients (35%).A significant proportion of patients had drug concentrations outside the therapeutic range. The Pharmacologic Optimization of PIs and NNRTIs (POPIN) study confirms that TDM trials are complex to interpret and statistically underpowered, with effectiveness better assessed through the clinical utility of a TDM result, whether normal or abnormal. Although TDM of PIs and NNRTIs may be useful in selected patients, routine and unselected use is not supported by current evidence.

Adult↗