Nonnucleoside reverse transcriptase inhibitors.
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Anti-HIV Agents↗
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Frequency of mutations conferring resistance to nucleoside reverse transcriptase inhibitors in human immunodeficiency virus type 1-infected patients in Korea.
A nested PCR and direct sequencing methods were used to define human immunodeficiency virus type 1(HIV-1) reverse transcriptase codons 41 to 219 in DNA from 127 peripheral blood mononuclear cell samples obtained from 35 patients treated with nucleoside reverse transcriptase inhibitors (NRTI). The follow-up period after the initiation of NRTI therapy was 61.8 +/- 31 months (mean and standard deviation). In addition to NRTI therapy, 32 of 35 patients were simultaneously treated with Korean red ginseng. The annual decrease in the CD4(+) T-cell count over 5 years was 13.2/microl. Twenty-eight (80%) of the 35 patients had mutations conferring resistance to NRTI. The frequencies of K70R, T215S/Y/F (i.e., mutation of T at codon 215 to S, Y, or F), D67N/E, K219Q, T69N/S/A, M41L, and L210W mutations conferring resistance to zidovudine were 57.6, 36.4, 36.4, 27.2, 24.2, 21.2, and 12.1%, respectively. Mutations conferring resistance to didanosine and lamivudine were detected in 2 (L74V and M184I; 14.2%) of 11 patients tested and in 4 (M184V; 57%) of 7 patients tested, respectively. In particular, the frequency of T69N/S/A increased sharply after more than 48 months of zidovudine monotherapy. However, Q151M was not detected. As the first report on the frequency of NRTI resistance mutations in Korea, our data suggest that genotypic antiretroviral drug testing should be considered for the design of better drug regimens to improve the management of HIV-1-infected patients.
Amino Acid Sequence↗
Observations of HIV-1 genotypic drug resistance in a trial of four reverse transcriptase inhibitors (Quattro Trial).
The Quattro Trial compared the use of four HIV-1 reverse transcriptase (RT) inhibitors (zidovudine, lamivudine, loviride and zalcitabine), given either as four-drug combination therapy or monotherapy, with 8-week cycles of each drug, with zidovudine/lamivudine dual therapy. Observations of resistance associated and other mutations in the RT gene were made to determine whether therapy failure could be explained by acquisition of these mutations and whether novel mutation patterns developed. As in the intent-to-treat analysis, the use of cyclical monotherapy gave a smaller reduction in plasma virus load at 64 weeks (0.4 log10 copies/ml below baseline) than the quadruple or dual therapy arms (1.3 and 0.8 log10 copies/ml below baseline). Cyclical therapy appeared to generate less genotypic resistance to zidovudine, loviride or zalcitabine than the other arms. Resistance to lamivudine (mutation M184V) developed rapidly in all three arms. Resistance to zidovudine was acquired by a larger proportion of subjects on dual therapy than on quadruple therapy. Resistance to loviride or zalcitabine was rarely observed. During lamivudine monotherapy the M184V mutation was rapidly acquired and viral load rebounded. Zalcitabine monotherapy initially selected M184V mutants, but these were lost as therapy continued. Novel mutations that may have been associated with combination or cyclical quadruple therapy were observed infrequently. There was no clear correlation between changes in response to therapy and the development of previously described resistance mutations or with novel mutations in the RT gene.
Acetamides↗
Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450.
Nevirapine (NVP), a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is concomitantly administered to patients with a variety of medications. To assess the potential for its involvement in drug interactions, cytochrome P-450 (CYP) reaction phenotyping of NVP to its four oxidative metabolites, 2-, 3-, 8-, and 12-hydroxyNVP, was performed. The NVP metabolite formation rates by characterized human hepatic microsomes were best correlated with probe activities for either CYP3A4 (2- and 12-hydroxyNVP) or CYP2B6 (3-and 8-hydroxyNVP). In studies with cDNA-expressed human hepatic CYPs, 2- and 3-hydroxyNVP were exclusively formed by CYP3A and CYP2B6, respectively. Multiple cDNA-expressed CYPs produced 8- and 12-hydroxyNVP, although they were produced predominantly by CYP2D6 and CYP3A4, respectively. Antibody to CYP3A4 inhibited the rates of 2-, 8-, and 12-hydroxyNVP formation by human hepatic microsomes, whereas antibody to CYP2B6 inhibited the formation of 3- and 8-hydroxyNVP. Studies using the CYP3A4 inhibitors ketoconazole, troleandomycin, and erythromycin suggested a role for CYP3A4 in the formation of 2-, 8-, and 12-hydroxyNVP. These inhibitors were less effective or ineffective against the biotransformation of NVP to 3-hydroxyNVP. Quinidine very weakly inhibited only 8-hydroxyNVP formation. NVP itself was an inhibitor of only CYP3A4 at concentrations that were well above those of therapeutic relevance (K(i) = 270 microM). Collectively, these data indicate that NVP is principally metabolized by CYP3A4 and CYP2B6 and that it has little potential to be involved in inhibitory drug interactions.
Antibodies↗
Phase I study of atevirdine, a nonnucleoside reverse transcriptase inhibitor, in combination with zidovudine for human immunodeficiency virus type 1 infection. ACTG 199 Study Team.
Twenty patients were enrolled in a phase I clinical trial of atevirdine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), given in combination with zidovudine for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Fifteen patients had received no previous antiretroviral therapy. HIV-1 isolates obtained at 6-week intervals were tested for sensitivity to atevirdine and zidovudine. Two patients developed a rash within 2 weeks of enrollment, and 1 of these developed concomitant fever and hepatitis. No hematopoietic, neurologic, or pancreatic toxicities were observed. Atevirdine had considerable initial interpatient pharmacokinetic variability. Forty-seven percent of patients treated with atevirdine plus zidovudine had increased CD4 lymphocyte counts, and HIV isolates from 62% of patients remained sensitive to atevirdine after 24 weeks of therapy. Atevirdine plus zidovudine was well-tolerated. Additional studies should be done to determine the role of atevirdine in the therapy for HIV infection.
Adult↗
HIV-1 RNA, CD4 cell count and the risk of progression to AIDS and death during treatment with HIV-1 reverse transcriptase inhibitors.
CONTEXT: There is little information available on the correlation between HIV-1 RNA level, CD4 cell count and the risk of progression to AIDS or death during treatment with reverse transcriptase inhibitors. OBJECTIVES: To define the correlation between HIV-1 RNA level, CD4 cell count and the 1 year risk of progression to AIDS or death. DESIGN: Pooled analysis of six randomized clinical trials of zidovudine/lamivudine versus control treatments. SETTING: Investigational sites in Europe, North America, Australia and South Africa. PATIENTS: The trials recruited 1488 adult HIV-1-infected male and female patients aged > or = 18 years, with inclusion CD4 cell count between 25 and 500 x 10(6) cells/l. Patients were either nucleoside analogue-naive or pre-treated, and at all stages of HIV-1 disease. MAIN OUTCOME MEASURES: : Progression (defined as all new and recurrent AIDS-defining events or death) was correlated with the HIV-1 RNA level and CD4 cell count during the first 8 to 52 weeks of treatment. RESULTS: During a median 1 year follow up, progression was largely restricted to patients with both low CD4 cell count (< or = 200 x 10(6) cells/l) and high HIV-1 RNA level (> 5000 copies/ml). There was an increase in the incidence of progression events with rises in HIV-1 RNA level > 5000 copies/ml and reductions in CD4 cell count under 200 x 10(6) cells/l. The events occurring with HIV-1 RNA < 5000 copies/ml were generally atypical. CONCLUSIONS: Progression to AIDS or death is rare for patients with HIV-1 RNA < or = 5000 copies/ml, particularly when CD4 cell count is more than 200 x 10(6) cells/l.
AIDS-Related Opportunistic Infections↗
Stavudine plus a non-thymidine nucleoside reverse transcriptase inhibitor as a backbone for highly active antiretroviral therapy.
Current guidelines for treatment of human immunodeficiency virus (HIV) disease favour the use of triple-drug combinations consisting of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor to achieve maximum suppression of HIV replication. There is considerable evidence for including one thymidine NRTI to target activated HIV host cells and one non-thymidine NRTI to target quiescent host cells as the backbone of such regimens. A number of recent studies have shown that stavudine in combination with didanosine or lamivudine is at least as effective as zidovudine-based combinations with regard to virological outcomes, with available data suggesting an enhanced effect on immunological outcome with stavudine-based combinations. When considered along with such advantageous characteristics of stavudine as infrequent and low-level resistance and good cerebrospinal fluid penetration, these findings indicate that stavudine in combination with didanosine or lamivudine should be considered for use as the backbone of multiple-agent highly active antiretroviral therapy (HAART).
Clinical Trials as Topic↗
Substituted naphthalenones as a new structural class of HIV-1 reverse transcriptase inhibitors.
A novel substituted naphthalenone (TGG-II-23A) has been found that inhibits HIV-1 infection of CEM-SS cells at concentrations that are not cytotoxic. Time of addition experiments indicate that TGG-II-23A functions at a stage of the HIV-1 life cycle at or near reverse transcription. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse transcriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A was specific for HIV-1 and failed to inhibit the replication of HIV-2. The binding site of TGG-II-23A appears to be in close proximity to that of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also resistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitive inhibitor that exhibits the same template:primer selectivity as other non-nucleoside inhibitors. TGG-II-23A therefore represents a new structural entry into the TIBO/Nevirapine class of inhibitors of HIV-1 reverse transcriptase.
Antiviral Agents↗
Kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-88204E.
The bis(heteroaryl)piperazine U-88204E is a potent inhibitor of HIV-1 reverse transcriptase (RT) and possesses excellent anti-HIV activity in HIV-1-infected lymphocytes grown in tissue culture. Enzymatic kinetic studies of the RNA- and DNA-dependent DNA polymerases of RT were carried out in order to determine whether the inhibitor interacts directly with the template:primer or deoxyribonucleotide triphosphate (dNTP) binding sites of the polymerase. The experimental results were analyzed using steady-state or Briggs-Haldane kinetics, by assuming that the template:primer binds to the enzyme first followed by the dNTP and that the polymerase functions processively. The results of the analysis show that the inhibitor acts as a mixed to noncompetitive inhibitor with respect to both the template:primer and the dNTP binding sites. The potency of U-88204E on the RNA-directed DNA polymerase activity depends on the base composition of the template:primer. The Ki values for the poly(rC):(dG)10-directed reactions were at least 7 times lower than the ones for reactions directed by poly(rA):(dT)10. The inhibitor did not inhibit the RNase H function of HIV-1 RT nor did it impair the RNA-directed DNA polymerase activity of HIV-2 RT. These data thus demonstrate the unique specificity of U-88204E for HIV-1 RT.
HIV Reverse Transcriptase↗
Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: a case-control study.
A case-control study was undertaken to determine risk factors for lactic acidosis in human immunodeficiency virus-infected patients treated with nucleoside reverse-transcriptase inhibitors (NRTIs). From May 1996 to June 2000, 9 patients with lactic acidosis (defined as a plasma lactic acid level of >5 mM and plasma pH of <7.38) were identified. Control patients were randomly selected from among a large cohort of patients who initiated a dual NRTI regimen in 1996 or after. Two factors were associated with an increased risk of lactic acidosis: first, a creatinine clearance of <70 mL/min before lactic acidosis (OR, 15.8 [range, 3.0-86.5], P<10(-4)), and, second, a low nadir CD4+ T lymphocyte count before the inception of NRTI therapy (OR, 8.4 [range, 1.2-infinity], P=.03). The total cumulative exposure to NRTIs was not associated with an increased risk of lactic acidosis, nor was the cumulative exposure to any of the 4 NRTIs studied. According to these results, monitoring of creatinine clearance, especially in patients with a low nadir CD4+ T lymphocyte count, could lead to modifications in antiretroviral therapy in order to diminish the risk of occurrence of lactic acidosis.
Acidosis, Lactic↗
Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy.
Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.
Base Sequence↗
Evidence of nucleoside analogue reverse transcriptase inhibitor--associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients.
To investigate if possible mitochondrial injury can be found in adipose tissue of nucleoside analogue reverse transcriptase inhibitor (NRTI)-treated patients, subcutaneous fat was taken from the buttocks of 24 HIV-positive patients and 8 HIV-negative controls. The content of mitochondrial DNA (mtDNA) was quantified using a Southern blot technique. Fat biopsies were examined by electron microscopy and screened by restriction fragment length polymorphism analysis for the presence of the nt 8344 and 3243 mtDNA point mutations. Age, sex, and body mass index did not differ between the HIV-negative controls, the HIV-positive patients currently treated with NRTIs (NRTI group, n = 19), and the HIV-positive patients without NRTIs (no-NRTI group, n = 5). The mean mtDNA content was 44% lower in the NRTI group compared with the no-NRTI group ( p =.01) but did not differ between the control group and the no-NRTI group. When the HIV-infected patients were stratified to a group with clinical signs of lipoatrophy at the biopsy site (LA group, n = 11) and a group without lipoatrophy (no-LA group, n = 13), the mean mtDNA content in the LA group was 39% lower than that in the no-LA group ( p =.02). No point mutations or deletions were observed. The adipocytes of patients with lipoatrophy contained multiple small lipid vacuoles, and the mitochondria harbored inclusions reminiscent of mtDNA cytopathies. mtDNA depletion and ultrastructural abnormalities of adipocytes suggest a link between mitochondrial damage, the use of NRTIs, and lipoatrophy in HIV-infected patients.
Adipose Tissue↗
Ritonavir/saquinavir plus one nucleoside reverse transcriptase inhibitor (NRTI) versus indinavir plus two NRTIs in protease inhibitor-naive HIV-1-infected adults (IRIS study).
OBJECTIVES: To compare the efficacy, tolerability and safety of a ritonavir 400 mg/saquinavir hard gel fomulation 400 mg twice daily versus an indinavir 800 mg once every 8 h containing first-line protease inhibitor (PI) treatment regimen. METHODS: Open, randomized, multicentre clinical trial. PI-naive patients received either ritonavir/saquinavir and one nucleoside reverse transcriptase inhibitor (NRTI) or indinavir and two NRTIs. Intention-to-treat (ITT) and on-treatment (OT) analyses were performed. RESULTS: The baseline characteristics of the study participants were similar in both arms, 67 patients (37%) were naive to antiretroviral treatment. The proportion of patients who achieved a plasma viral load below the level of detection of 400 copies/ml at week 48 was 43% (39/90) in the ritonavir/saquinavir arm and 63% (57/90) in the indinavir arm (P=0.005, I
Acquired Immunodeficiency Syndrome↗
An LC-MS-MS method for the determination of nevirapine, a non-nucleoside reverse transcriptase inhibitor, in human plasma.
A sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS-MS) method has been developed to measure the levels of the HIV-1 non-nucleoside reverse transcriptase inhibitor nevirapine (NVP) in human plasma. The analyte and internal standard (IS) are isolated from plasma by a simple perchloric acid precipitation of plasma proteins followed by centrifugation. LC-MS-MS in positive mode used pairs of ions at m/z of 267/226 for NVP and 628/421 for the IS, respectively. Two linear calibration curves were established for quantitation of NVP with the low curve ranging from 25 to 1000 ng/ml and the high curve ranging from 1000 to 10,000 ng/ml. Mean inter- and intra-assay coefficients of variation (CVs) over the ranges of the two standard curves were less than 10%. The overall recovery of NVP was 92.4%.
Anti-HIV Agents↗
Factors related to virologic failure among HIV-positive injecting drug users treated with combination antiretroviral therapy including two nucleoside reverse transcriptase inhibitors and nevirapine.
Treatment strategies in human immunodeficiency virus (HIV)-positive active injecting drug users (IDUs) must take into account their lifestyles, that often result in low adherence to therapy. The nonnucleoside reverse transcriptase inhibitors (NNRTI) offer simpler treatment regimens, but the appearance of drug resistance during treatment failure may cause high levels of cross-resistance to all NNRTIs. We adopted a combination therapy of two NRTIs and nevirapine (NVP) for treatment of IDU patients to evaluate its feasibility in such patients. From October 1998 to December 1999, demographic, clinical, and laboratory data from 80 IDUs on this regimen were collected. Fisher's exact test, Kaplan Meier method, and Cox model were used for statistical analysis. Overall, 20 IDUs discontinued the treatment because of side effects and 20 IDUs experienced treatment failure. Considering the treatment failure as an end point, 55.6% (95% confidence interval [CI]: 37.9%-72.6%) of patients was still undergoing treatment after 12 months compared to 44.6% (31.8%-58.6%) when discontinuation was also taken into account. An increasing trend over time was observed in the CD4+ lymphocyte count, among failing and nonfailing IDUs. By multivariate analysis, baseline HIV-RNA, treatment breaks and low adherence and active injecting drug use turned out to be significantly associated with treatment failure. Our results show that continuing injecting drug use and treatment breaks are the main factors that can lead to treatment failure in IDUs and easily to NNRTI class resistance.
Adult↗
The Y181C mutant of HIV-1 reverse transcriptase resistant to nonnucleoside reverse transcriptase inhibitors alters the size distribution of RNase H cleavages.
We investigated the effects of the nonnucleoside reverse transcriptase inhibitor-resistant mutant Y181C on RNA 5'-end-directed RNase H cleavage by HIV-1 reverse transcriptase, using an RNA.DNA hybrid in which a radiolabeled RNA 5' end was recessed. Y181C produced a higher ratio of secondary (9 nucleotide long) to primary (18 nucleotide long) products than wild type. When the RNA was 3'-end-labeled, Y181C generated a long product, which results when secondary cleavage precedes the primary. When using an RNA.DNA hybrid in which the labeled RNA 5' end and DNA 3' end were flush, formation of secondary product by both enzymes was inhibited. Under these conditions, Y181C cleaved closer to the RNA 5' end than wild type. Studies with this substrate labeled at the RNA 3' end showed that Y181C is no more likely than wild type to cleave toward the RNA 3' end. Thus, Y181C RT has a strong preference to cleave in the direction of the RNA 5' end even when secondary cleavage is prevented, resulting in a disruption of the normal sequence of primary followed by secondary cleavages.
3' Untranslated Regions↗
Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors.
Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 microM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 microM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 microM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 microM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 microM) is not associated with mitochondrial toxicity.
Adenine↗
Exposure of normal and transformed cells to nevirapine, a reverse transcriptase inhibitor, reduces cell growth and promotes differentiation.
Endogenous, nontelomeric reverse transcriptase (RT) is encoded by two classes of repeated elements: retrotransposons and endogenous retroviruses. Expression of RT-coding genes is generally repressed in differentiated nonpathological tissues, yet is active in the mammalian germ line, embryonic tissues and tumor cells. Nevirapine is a non-nucleoside RT inhibitor with a well-characterized inhibitory activity on RT enzymes of retroviral origin. Here, we show that nevirapine is also an effective inhibitor of the endogenous RT in murine and human cell lines. In addition, progenitor and transformed cells undergo a significant reduction in the rate of cell growth upon exposure to nevirapine. This is accompanied by the onset of differentiation, as depicted in F9 and C2C7 progenitor cells cultures in which nevirapine triggers the expression of differentiation-specific markers. Consistent with this, an extensive reprogramming of cell cycle gene expression was depicted in nevirapine-treated F9 cultures. Furthermore, nevirapine exposure rescued the differentiation block present in acute myeloid leukemia (AML) cell lines and primary blasts from two AML patients, as indicated by morphological, functional and immunophenotypic assays. The finding that an RT inhibitor can modulate cell proliferation and differentiation suggests that RT may represent a novel target in the development of therapeutical approaches to neoplasia.
3T3 Cells↗