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At least 19 recordsLinked to original sources
PubMed2004

Comparison of the dynamics of resistance-associated mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors after cessation of antiretroviral combination therapy.

The dynamics of mutations associated with resistance to antiretroviral drugs were analyzed after cessation of therapy. The results showed that the kinetics of the shift to wild-type amino acid residues were significantly faster for protease inhibitors, intermediate for nonnucleoside reverse transcriptase inhibitors, and slower for nucleoside reverse transcriptase inhibitors.

Anti-HIV Agents↗
PubMed1995

Interface peptides as structure-based human immunodeficiency virus reverse transcriptase inhibitors.

Reverse transcriptases from both human immunodeficiency viruses type 1 and 2 are obligatory dimers. A tryptophan-rich repeat motif that is highly conserved between these proteins, as well as in the reverse transcriptase from simian immunodeficiency virus, has been postulated to be involved in hydrophobic subunit interactions. A synthetic 19-mer peptide covering part of this tryptophan repeat motif was recently shown to inhibit human immunodeficiency viruses type 1 reverse transcriptase subunit dimerization (Divita, G., Restle, T., Goody, R. S., Chermann, J.-C., and Baillon, J. G. (1994) J. Biol. Chem. 269, 13080-13083). In the present study, we show that the same peptide can also inhibit human immunodeficiency virus type 2 reverse transcriptase subunit dimerization, suggesting that the same inhibitors might be used as agents against both viruses as well as against variants of human immunodeficiency virus type 1 that differ from the variant against which they were developed. Under appropriate experimental conditions, e.g. at acidic pH, this peptide is also able to induce the dissociation of the enzyme from human immunodeficiency virus type 1.

Amino Acid Sequence↗
PubMed1995

Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors.

Reverse transcriptase (RT) is an appropriate target for anti-HIV chemotherapy. In recent years several entirely new leads for the design of different structural classes of HIV-1-specific RT inhibitors were provided (also called non-nucleoside RT inhibitors or NNRTI). We performed profound studies on (i) the structure-antiviral activity relationship of TSAO (a prototype NNRTI compound), (ii) the biochemical and molecular mechanism of anti-viral action of TSAO and other NNRTI's, (iii) metabolism and antimetabolic effects of TSAO's in cell culture, and (iv) the pharmacokinetic properties of TSAO in mice. In addition, the molecular basis of resistance development of HIV-1 RT against other NNRTI's have also been profoundly studied. A mapping of the resistance mutations in the binding pocket of the RT and the sensitivity/resistance spectrum of the most important NNRTI's that are subject of clinical trials have been determined. Based on the information that became evident from these studies, a molecular model of interaction of the NNRTI inhibitor TSAO with the binding pocket in the HIV-1 reverse transcriptase has been proposed, and now provide the rational basis for the development of second generation TSAO molecules that may become suppressive to mutant HIV-1 strains. Also, resistance development could be markedly delayed, modulated, attenuated, or even fully suppressed by at least two different original approaches: (i) the knock-out drug concentration principle that exploits the limited capacity of mutant HIV-1 reverse transcriptases to respond to high NNRTI drug concentrations and (ii) the rational paired drug combination therapy that exploits the mutually exclusive sensitivity/resistance properties of NNRTI drugs against the different NNRTI-specific resistance mutations in the RT. Our findings have provided us with several powerful tools to have a more efficient chemotherapeutic impact on the HIV-1 infection and to better control the emergence of viral resistance.

Animals↗
PubMed2005

Triple nucleoside reverse transcriptase inhibitor- vs. nonnucleoside reverse transcriptase inhibitor-containing regimens as first-line therapy: efficacy and durability in a prospective cohort of French HIV-infected patients.

OBJECTIVE: Based on the short-term results of the AIDS Clinical Trials Group (ACTG) A5095 trial, zidovudine (ZDV)/lamivudine (3TC)/abacavir (ABC) is no longer recommended as a first-line antiretroviral regimen. Data on the efficacy of this triple nucleoside reverse transcriptase inhibitor (NRTI) combination compared with the gold-standard nonnucleoside reverse transcriptase inhibitor (NNRTI) regimen could provide important information. METHODS: Patients were selected from three prospective cohorts of patients who received first-line therapy with ZDV/3TC plus an NNRTI or ABC, started after January 1998. Immunovirological changes and the proportion of treatment discontinuations were compared between groups. RESULTS: Of the 380 patients, 190 started on ABC [the triple-NRTI group (3N)] and 190 on NNRTI. At baseline, there was no statistical difference between the NNRTI and 3N groups for age (mean=38 years), sex (66% male) or CD4 cell count (mean=305 cells/muL). Mean baseline plasma HIV-1 viral load (pVL) was higher in the 3N group (4.6 vs. 4.3 log10 HIV-1 RNA copies/mL: P<0.01). Lower and higher estimates of median pVL decrease at month 24 were 2.05 and 4.76 log10 copies/mL in the 3N group, and 1.73 and 4.31 log10 copies/mL in the NNRTI group (not significant). CD4 cell count evolution did not differ between groups. Treatment discontinuation occurred in 45% vs. 44% of patients in the NNRTI and 3N groups, respectively, after median durations of 9 and 4 months, respectively (P=0.02). CONCLUSIONS: In this prospective cohort, 3N and NNRTI regimens as first-line therapy produced similar immunovirological responses.

Adult↗
PubMed2000

[Current situation of nucleoside reverse transcriptase inhibitors].

Nucleosidic reverse transcriptase inhibitors were the first class of drugs to be used for the treatment of HIV disease. Recent data on the complex pathways allowing the virus to adapt to the drugs will lead to better management of the phenomena. Similarly, better understanding of the mechanism of their toxicity will allow safer use. As these drugs are simple to use, and have a sustained effect over time with reasonable tolerance, nucleosidic reverse transcriptase inhibitors are currently the main contributors to multi-drug anti-HIV regimens. Reverse transcriptase inhibitors are currently the main contributors in multi-drug anti-HIV regimens.

Anti-HIV Agents↗
PubMed2004

TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 microM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.

Cell Line↗
PubMed2004

Virological significance, prevalence and genetic basis of hypersusceptibility to nonnucleoside reverse transcriptase inhibitors.

Nonnucleoside reverse transcriptase inhibitors (NNRTI) are used to treat HIV-infected individuals in combination with nucleoside analogues (NRTI) and protease inhibitors. Long-term treatment with antiretroviral agents results in the emergence of strains with decreased susceptibility (resistance) to the drugs and is one of the major factors in loss of drug efficacy. Conversely, there have been recent reports of HIV strains with increased susceptibility (hypersusceptibility) to NNRTIs. These isolates emerge in patients on long-term antiretroviral therapy particularly in individuals receiving NRTIs. The prevalence of NNRTI hypersusceptibility ranges between 17.5 and 50% in NRTI-treatment experienced compared to 10% in NRTI-naïve patients. There is an inverse correlation between NNRTI hypersusceptibility and phenotypic NRTI resistance and a direct correlation between the number of NRTI resistance mutations present in the HIV reverse transcriptase. Re-sensitisation of phenotypic NNRTI resistance has been reported by NRTI mutations and is not likely to be detected using genotypic resistance assays. Recent studies demonstrate that NNRTI hypersusceptible virus at baseline is likely to predict better virological outcomes in patients on NNRTI-based salvage regimens compared to patients with NNRTI susceptible virus. These studies have implications for the sequence of antiretroviral drug use where patients may benefit from NRTI therapy before the introduction of NNRTIs, however more studies are needed to examine this treatment rationale.

Drug Resistance, Viral↗
PubMed2003

Bench-to-bedside review: severe lactic acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors.

Nucleoside reverse transcriptase inhibitors (NRTIs) are effective antiretroviral therapy for the treatment of HIV-infected patients. NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis. In the present review, we describe the underlying mechanism of NRTI-induced toxicity and the main clinical features of this infrequent, but severe, emerging complication. We also summarise experimental data and clinical observations that support the use of L-carnitine supplementation to reverse NRTI-induced mitochondrial impairment.

Acidosis, Lactic↗
PubMed1998

Immunologic effects of combined protease inhibitor and reverse transcriptase inhibitor therapy in previously treated chronic HIV-1 infection.

OBJECTIVE: To evaluate the efficacy of combination protease and reverse transcriptase inhibitor therapy in correcting HIV-1-induced lymphocyte subset abnormalities in previously treated adults. DESIGN: A 48-week observational study of lymphocyte subsets in 12 participants in the Multicenter AIDS Cohort Study who were already taking at least one reverse transcriptase inhibitor and added a protease inhibitor to their treatment regimen. Comparison groups were HIV-seronegative homosexual men, HIV-seronegative heterosexual men, and homosexual HIV-1-infected men who were long-term non-progressors. METHODS: Three-color immunofluorescence and monoclonal antibodies were used to assess HIV-1-induced lymphocyte subset alterations related to immune deficiency and immune activation. Plasma HIV-1 RNA levels were monitored to assess suppression of viral replication. RESULTS: CD4+ cell counts significantly increased and lymphocyte activation measured as CD38 and HLA-DR expression on CD8+ T cells significantly decreased by 48 weeks. CD4+ cell values remained abnormal even in those who were fully suppressed. Some T-cell activation markers decreased to levels observed in long-term non-progressors. The increase in CD4+ T-cell numbers reached a plateau by week 24, but the increase in resting HLA-DR- CD38-T cells was sustained through week 48. Proportions of CD45RA+ CD62L-selectin+ and CD28+ CD4+ T-cell subsets and Fas expression were not abnormal at baseline compared with seronegative homosexual controls. CONCLUSIONS: The most significant impact of suppression of viral replication was reversal of T-cell activation. However, normalization of lymphocyte subset perturbations associated with chronic HIV-1 infection was not achieved after 1 year of treatment with current combination antiretroviral regimens. More profound viral suppression, therapy for longer than 1 year, or immunologic augmentation may be needed to fully reverse the abnormalities.

Adult↗
PubMed2002

Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs), particularly nevirapine, have been associated with hepatotoxicity. We performed a retrospective study to determine the incidence of NNRTI hepatotoxicity in a group of HIV-infected patients from a New York City practice. These patients are predominantly homosexual white males. We also analyzed the effect of coinfection with hepatitis B (HBV) or hepatitis C (HCV) virus. In total, 272 patients received NNRTIS: 40 (15%) received delavirdine, 91 (33%) received efavirenz, and 141 (52%) received nevirapine. Of the patients with known hepatitis status, 18 of 190 (9%) were coinfected with HBV, and 24 of 205 were coinfected (12%) with HCV. The overall rate of grade 3 to 4 elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) was 3 of 272 (1.1%) and did not differ significantly among the three NNRTIs. HBV or HCV was not associated with a significant increase in AST or ALT elevations. We conclude that NNRTIs are relatively free from hepatotoxicity in this population, despite the presence of coinfection with HBV or HCV.

Alanine Transaminase↗
PubMed2005

Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors.

Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity. Although well studied outside of the central nervous system, no investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine and lamivudine, 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV- controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV- controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment (r = -.41, P = .06). Levels of NAA were not related to length of zidovudine/lamivudine treatment (r = -.04, P = .44). Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration. Measurement of brain metabolites sensitive to impairments in energy metabolism, including NAA, may aid in early detection of subclinical NRTI-mediated mitochondrial toxicity.

Adult↗
PubMed2005

Evaluation of an oligonucleotide ligation assay for detection of mutations in HIV-1 subtype C individuals who have high level resistance to nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors.

The oligonucleotide ligation assay (OLA) has been proposed as an affordable alternative to sequence-based HIV-1 drug resistance testing in resource poor settings. The aim was to evaluate OLA for detecting mutations K103N, Y181C, K65R, Q151M, M184V and T215Y/F in subtype C. Forty-four subtype C and 8 subtype B HIV-1 positive individuals were analysed using the ViroSeqtrade mark HIV-1 genotyping assay (Applied Biosystems, Foster City, CA). A one-step RT-PCR and nested PCR were performed using subtype B specific primers from the OLA kit (NIH AIDS Research and Reference Reagent Program). Seventy-eight subtype C sequences were used to design subtype C specific primers. Ligation and detection steps were followed according to OLA kit protocol. For codons, K103N, Y181C, K65R, Q151M, M184V and T215Y/F, four or more mismatches compared to the probe or mismatches less than four bases from the ligation site were not tolerated. Results revealed accurate identification of mutations in 2/10, 4/9 3/9, 6/7, 2/7 and 6/7 VQA samples and 5/20, 4/17 0/20, 18/24, 5/24 and 13/24 subtype C positive individuals, respectively. It was concluded that the probes and primers in the NIH reference kit would need modification to optimize detection of mutations in subtype C individuals.

Anti-HIV Agents↗
PubMed2006

A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial.

BACKGROUND: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. METHODS: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. FINDINGS: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). INTERPRETATION: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.

Adult↗
PubMed1992

3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors.

Nonnucleoside reverse transcriptase (NNRT) inhibitors (R82913; (+)-S-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)- imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione; Cl-TIBO; and BI-RG-587, nevirapine) were used to select resistant human immunodeficiency virus type 1 (HIV-1) variants by passage in cell cultures of wild-type or 3'-azido-3'-deoxythymidine (zidovudine; AZT)-resistant strains. Similar to other NNRT inhibitors, Cl-TIBO induced a single mutation (Y181 to C) in reverse transcriptase (RT) that accounted for the resistance. BI-RG-587 induced a different mutation (V106-->A) in AZT resistance backgrounds. A series of viable HIV-1 variants was constructed by site-directed mutagenesis of the RT, which harbored multiple drug resistance mutations, including Y181 to C. HIV-1 that was co-resistant to NNRT inhibitors and 2',3'-dideoxyinosine resulted when a 2',3'-dideoxyinosine resistance mutation (L74 to V) was also present in RT. By contrast, however, the Y181 to C mutation in an AZT resistance background significantly suppressed resistance to AZT, while it conferred resistance to NNRT inhibitors. However, the V106-->A substitution did not cause suppression of preexisting AZT resistance. Since certain combinations of nucleoside analogs and NNRT inhibitors might result in the development of co-resistance, careful analysis of clinical isolates obtained during combination therapy will be needed to determine the potential significance of these observations.

Antiviral Agents↗
PubMed2006

A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors.

Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.

Administration, Oral↗
PubMed1999

Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype.

OBJECTIVES: To study the effect of the interruption of reverse transriptase inhibitor (RTI) therapy or a switch from RTI to protease inhibitors, on the genotypic drug-resistance pattern of plasma HIV-1. METHODS: Nine patients who completely stopped all medication, and five patients who switched from a treatment with RTI to a regimen containing protease inhibitors only, were studied. Direct sequencing of the plasma HIV-1 RT and protease gene was performed on follow-up samples taken before and after the interruption of treatment. RESULTS: Comparison of the amino acid sequence of the RT and protease genes in successive samples showed the rapid reappearance of wild-type viral variants in 12 of the 14 patients studied. Wild-type virus replaced the mutant strains 14 days to 2 months after the interruption of therapy, even in patients with a long treatment history. CONCLUSION: The results of this study indicate the sustained lower fitness of mutant strains in vivo. As a result, wild-type virus remains capable of outcompeting the RT or protease mutant strains very fast after removal of the drug. These findings highlight the importance of 'treatment history' in addition to genotypic and phenotypic markers determined at one time-point, when making therapeutic decisions for patients.

Amino Acid Substitution↗