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PubMed2003

Toxicity of non-nucleoside analogue reverse transcriptase inhibitors.

The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.

Alkynes↗
PubMed2004

Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics.

Nucleoside reverse transcriptase inhibitor (NRTI)-induced cardiomyopathy has been suggested to reflect mitochondrial targets of drug toxicity. The prevailing hypothesis is that, through structural mimicry, the NRTIs are mistaken as substrates for DNA polymerase and incorporated into replicating DNA, where they cause truncation of the elongating strand. Although there exist five forms of nuclear DNA polymerase, mitochondria possess solely DNA polymerase-gamma (pol-gamma), which is a preferred target for most NRTIs. Consequently, mitochondria are particularly susceptible to inhibition of DNA replication by the NRTIs, which is consistent with the phenotype of mitochondrial depletion and metabolic failure in affected patients. However, the DNA pol-gamma hypothesis by itself fails to explain the entire array of metabolic deficiencies associated with NRTI-induced disorders. In this article, we review the published literature regarding the direct effects of NRTIs on various mitochondrial targets and suggest the possibility that the initiating event in NRTI-induced cardiomyopathy is a direct mitochondrial toxicity rather than inhibition of mitochondrial DNA pol-gamma. The goal of this review is to encourage a discussion of the cause of NRTI-induced mitochondrial cardiomyopathy to include a fresh consideration of all possible targets and integrating pathways that are involved in establishing mitochondrial bioenergetic fidelity and metabolic capacity in the affected myocardium.

Animals↗
PubMed2002

Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors.

BACKGROUND: Some nucleoside analogue reverse transcriptase inhibitors (NRTI) may cause depletion of mitochondrial (mt) DNA in liver by inhibiting polymerase-gamma. mtDNA depletion may contribute to lactic acidosis, steatohepatitis and liver failure. OBJECTIVE: To evaluate the long-term mitochondrial toxicity of NRTI combinations. METHODS: The HepG2 human hepatoma cell line was cultivated in the presence of zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), zidovudine (ZDV) and efavirenz at concentrations equivalent to steady-state peak plasma levels (C ), and also in one-third and 10 times C. The NRTI were added to the medium alone or in combination. Control cells were incubated without any NRTI or with efavirenz. Cell growth, lactate production, intracellular lipid droplets, mtDNA and the mtDNA-encoded respiratory chain subunit COX II were monitored over a period of up to 30 days. RESULTS: Time- and dose-dependent mtDNA depletion was observed with ddC > ddI > d4T and mtDNA depletion preceded or coincided with a decline in COX II expression, a decrease in cell growth, increased lactate production and increased intracellular lipids. 3TC and efavirenz did not affect any measurement. ZDV increased lactate moderately and cell growth was inhibited, despite normal mtDNA and COX II levels. The negative effects on some measurements were more pronounced in the 3TC-ZDV and ddC-d4T combinations, than in the single-NRTI incubations. The combination of ddI-d4T was not more toxic than ddI alone. Mitochondrial damage by ZDV, d4T, ddI, and ddC did not reach steady-state by day 25. Using a Southern blot technique, mtDNA deletions were never observed. CONCLUSION: The data indicate additive or synergistic long-term mitochondrial toxicity in some NRTI combinations.

Acidosis, Lactic↗
PubMed2006

HIV-1 reverse transcriptase plus-strand initiation exhibits preferential sensitivity to non-nucleoside reverse transcriptase inhibitors in vitro.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are highly specific and potent allosteric inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. NNRTIs inhibit reverse transcription in a substrate length-dependent manner in biochemical assays and in cell-based HIV-1 replication assays, suggesting a stochastic inhibitory mechanism. Surprisingly, we observed that NNRTIs potently inhibited plus-strand initiation in vitro under conditions in which little or no inhibition of minus-strand DNA synthesis was observed. In assays that recapitulated the initiation of plus-strand DNA synthesis, greater inhibition was observed with an RNA PPT primer than with a DNA primer of corresponding sequence and with wild-type reverse transcriptase but not with NNRTI-resistant enzymes. Structural elements that dictate sensitivity to NNRTIs were revealed using modified plus-strand initiation substrates. The data presented here suggest that specific inhibition of plus-strand initiation may be an important mechanism by which NNRTIs block HIV-1 replication.

Alkynes↗
PubMed2001

Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV type 1 (HIV-1) reverse transcriptase (RT). Yeast grown in the presence of many of these drugs exhibited dramatically increased association of the p66 and p51 subunits of the HIV-1 RT as reported by a yeast two-hybrid assay. The enhancement required drug binding by RT; introduction of a drug-resistance mutation into the p66 construct negated the enhancement effect. The drugs could also induce heterodimerization of dimerization defective mutants. Coimmunoprecipitation of RT subunits from yeast lysates confirmed the induction of heterodimer formation by the drugs. In vitro-binding studies indicate that NNRTIs can bind tightly to p66 but not p51 and then mediate subsequent heterodimerization. This study demonstrates an unexpected effect of NNRTIs on the assembly of RT subunits.

Amino Acid Substitution↗
PubMed2004

The rise and fall of triple nucleoside reverse transcriptase inhibitor (NRTI) regimens.

Triple nucleoside reverse transcriptase inhibitor (NRTI) regimens have attracted much interest due to their potential to (1) simplify dosing, with potential gains in adherence to treatment, and (2) reduce or even reverse dyslipidaemia associated with protease inhibitor (PI) therapy. A variety of triple NRTI combinations have been investigated, in both antiretroviral-naive and antiretroviral-experienced HIV-infected patients. Many of these trials have generated disappointing results, and some have been prematurely discontinued due to poor efficacy. This article reviews the background to the development of triple NRTI regimens, and the mounting evidence that this approach is suboptimal for antiretroviral-naive patients. Indeed, some triple NRTI regimens should never be used in this population. A role for triple NRTI combinations as a simplification strategy in treatment-experienced patients whose HIV is well controlled has been suggested, but emerging evidence indicates that such an approach can, under adequate selection pressure, lead to the emergence of mutations and viral load rebound. This commentary discusses the factors that appear to influence patients' responses to triple NRTI therapy, and their implications for patient selection.

Clinical Trials as Topic↗
PubMed1996

Synthesis and biological evaluation of certain alkenyldiarylmethanes as anti-HIV-1 agents which act as non-nucleoside reverse transcriptase inhibitors.

Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these proved to be 3',3"-dibromo-4',4"-dimethoxy-5'5"-bis(methoxycarbonyl)-1,1-diphenyl-1-+ ++heptene (8) ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC50 value of 7.1 microM and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 microM) with poly(rC).oligo(dG), but not with poly(rA).oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcriptases containing non-nucleoside reverse transcriptase inhibitor resistance mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutations in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic activity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combination with AZT or with other NNRTIs that are made ineffective by mutations at residues which do not confer resistance to ADAM 8.

Amino Acid Sequence↗
PubMed2004

Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors.

Since their discovery, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have become one of the cornerstones of highly active anti-retroviral therapy (HAART). Currently, three NNRTI agents, efavirenz, nevirapine and delavirdine are commercially available. Efavirenz and nevirapine, used in combination with nucleoside reverse transcriptase inhibitors (NRTIs), provide durable regimens with efficacy comparable to protease inhibitor (PI) containing therapies. When virological failure occurs following treatment with an NNRTI, the resistance mutations can confer reduced sensitivity to the entire agent class. Therefore, the strategy for the development of next generation NNRTIs has been to focus on compounds which have improved potencies against the clinically relevant viral mutants. Agents with improved virological profiles and which maintain the ease of administration and favorable safety profiles of the current agents should find use in anti-retroviral naïve patients as well as in components of salvage regimens in the anti-retroviral experienced patient. This review summarizes the recent developments with compounds in clinical trials as of January 2002 as well as to summarize information on new agents appearing in the primary and patent literature between January 2001 and December 2002.

Anti-HIV Agents↗
PubMed2000

Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?

Nucleoside reverse transcriptase inhibitors suppress HIV replication by blocking reverse transcriptase, an RNA-dependent DNA polymerase. These drugs can also affect cellular and mitochondrial DNA polymerases. Mitochondrial DNA polymerase gamma is particularly sensitive to nucleoside reverse transcriptase inhibitors, and the majority of adverse effects caused by nucleoside reverse transcriptase inhibitors are most likely caused by mitochondrial dysfunction. This article reviews the recent clinical implications of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity and discusses options for management.

Journal Article↗
PubMed1997

Cross-resistance analysis and molecular modeling of nonnucleoside reverse transcriptase inhibitors targeting drug-resistance mutations in the reverse transcriptase of human immunodeficiency virus.

Oxathlin carboxanilide analogs (UC) and alpha APA, compounds recognized as nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI), were evaluated for activity against the human immunodeficiency virus (HIV-1) and drug-resistant variants. These NNRTIs are structurally diverse but potent inhibitors of HIV-1 with efficacy in the nanomolar to low micromolar concentrations. They interact at a specific site in the pain domain of the p66 subunit of RT. Treatment of HIV-1 infected cell cultures with UC compounds resulted in the selection of drug-resistant viruses bearing specific amino acid changes at 100, 101, 103, 106, and/or 181. Since Y181C and L1001 are the most commonly observed resistance-engendering mutations, RT enzymatic analysis was correlated with molecular modeling to glean information on the structural interactions between these NNRTIs and RT. Information derived from these studies will facilitate rational drug design and the selection of complementary anti-HIV drugs for combination therapy.

Drug Resistance, Microbial↗
PubMed2006

Initial highly-active antiretroviral therapy with a protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor: discrepancies between direct and indirect meta-analyses.

BACKGROUND: The optimum treatment choice between initial highly-active antiretroviral therapy (HAART) with a protease inhibitor (PI) versus a non-nucleoside reverse transcriptase inhibitor (NNRTI) is uncertain. An indirect analysis reported that PI-based HAART was better than NNRTI-based HAART. However, direct evidence for competing interventions is deemed more reliable than indirect evidence for making treatment decisions. We did a meta-analysis of head-to-head trials and compared the results with those of indirect analyses. METHODS: 12 trials of at least 24 weeks' duration directly compared NNRTI-based versus PI-based HAART in HIV-infected patients with limited or no previous exposure to antiretrovirals. We also identified six trials of NNRTI-based HAART and eight trials of PI-based HAART, each versus two NRTI regimens. We analysed the outcomes of virological suppression, death or disease progression, and withdrawals due to adverse events. FINDINGS: In the direct meta-analysis, NNRTI-based regimens were better than PI-based regimens for virological suppression (OR 1.60, 95% CI 1.31-1.96). The difference was reduced in higher-quality trials, but still favoured NNRTI-based HAART. There were no differences in death or disease progression (0.87, 0.56-1.35) or withdrawal because of adverse events (0.68, 0.43-1.08). By contrast, in indirect analyses NNRTI-based HAART was worse than PI-based HAART for virological suppression (0.26, 0.07-0.91). There were no significant differences for death or disease progression (1.28, 0.56-2.94) and withdrawals because of adverse events (1.46, 0.66-3.24). When trials of delavirdine were excluded, similar results were produced. INTERPRETATION: Results from direct analyses suggested that NNRTI-based HAART was more effective than PI-based HAART for virological suppression and was similar to PI-based HAART for clinical outcomes. Indirect comparisons could be unreliable for complex and rapidly evolving interventions such as HAART.

Adult↗
PubMed2006

The K101P and K103R/V179D mutations in human immunodeficiency virus type 1 reverse transcriptase confer resistance to nonnucleoside reverse transcriptase inhibitors.

Genotypic patterns associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in the absence of well-characterized resistance mutations were identified using a database (n > 47,000) of phenotype-genotype data. Among samples with no known NNRTI mutations, the most resistant samples contained K101P (n = 35) or a combination of K103R and V179D (n = 41). Site-directed mutagenesis confirmed the importance of these mutations.

Amino Acid Substitution↗
PubMed2007

Non-nucleoside reverse transcriptase inhibitors: a review.

Non-nucleoside reverse transcriptase inhibitors form the backbone of antiretroviral treatment for many HIV-infected individuals. The tolerability, pill burden and efficacy associated with this class of agents make them a frequent choice for first-line therapy. Here we review nevirapine and efavirenz in terms of efficacy, resistance and toxicity, focusing particularly on the use of nevirapine to prevent mother-to-child transmission in developing countries.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Simple, short peptide derivatives of a sulfonylindolecarboxamide (L-737,126) active in vitro against HIV-1 wild type and variants carrying non-nucleoside reverse transcriptase inhibitor resistance mutations.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) active against NNRTI-resistant mutants were obtained by introducing two methyl groups at positions 3 and 5 of the benzenesulfonyl moiety of L-737,126 (1) and coupling one to three glycinamide/alaninamide units to its carboxyamide function. In cell-based assays, the new derivatives showed activities against HIV-1 wild type and NNRTI-resistant mutants [Y181C, K103N-Y181C, and triple mutant (K103R, V179D, P225H) highly resistant to efavirenz] superior to that of the parent indole derivative 1.

Anti-HIV Agents↗
PubMedDate not supplied

Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy.

Nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are the cornerstones of current AIDS therapy, but extensive use brought mitochondrial side effects to light. Clinical experience, pharmacological, cell, and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in target tissues are observed. Organ-specific pathological changes or diverse systemic effects result from and are frequently attributed to HAART in which NRTIs are included. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors.

OBJECTIVE: To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy. DESIGN: The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults. METHODS: Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed. RESULTS: Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log10 or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1-2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with > or = 3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus (P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), > or = 4 mutations were required to diminish virological response significantly (P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense HIV assay and the Antivirogram assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/microl by weeks 12-28. CONCLUSIONS: Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review.

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.

Adult↗
PubMed2001

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

Although understanding of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance is less clearly established than that of other classes of antiretroviral drugs, certain facts have been established. The treatment-associated genetic mutation profiles of the available NNRTIs have been mapped, and resistance has been found to develop rapidly after initiation of NNRTI therapy. Despite the chemical diversity of the NNRTIs, cross-resistance among agents of this class is nearly universal. Although the viral replicative capacity ("fitness") of NNRTI-induced viral variants has not been extensively studied, available data suggest that NNRTI-selected mutations confer little damage to viral fitness, and thus a single point mutation produces a strain that is both resistant and fit. Furthermore, with continued therapy, viral evolution persists, creating species with greater numbers of mutations and higher level phenotypic resistance. Taken together, these facts suggest that continued use of NNRTIs after emergence of resistance will produce variants of complex mutational patterns that limit future treatment options, and, therefore, strong consideration should be given to discontinuing NNRTIs after virologic failure is confirmed. This article describes the scientific literature establishing the efficacy and limitations of NNRTI therapy and attempts to define a role for this class of drug in the long-term treatment of HIV-1 disease.

Alkynes↗