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PubMed2004

Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects.

OBJECTIVE: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. METHODS: : HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add NVP and/or HU to the triple NRTI backbone of zidovudine plus lamivudine plus abacavir. Primary endpoint was treatment failure, defined as having plasma HIV RNA levels > 50 copies/ml after week 24, or discontinuation of randomized treatment. Follow-up was 72 weeks. RESULTS: For the 229 subjects, median plasma HIV-1 RNA was 4.61 log10 copies/ml and median CD4 cell count was 269 x 10 cells/l. NVP users reached plasma HIV-1 RNA < 50 copies/ml more rapidly than subjects using no NVP (log-rank test; P = 0.011). In the as-treated analysis, 21.6% of subjects using NVP versus 48.8% using no NVP reached the primary endpoint (P = 0.013). In the intent-to-treat analysis, 83.3% of subjects using HU versus 73.0% using no HU experienced treatment failure (P = 0.060), while no difference was observed in the as-treated analysis (34.5 versus 36.7%). Differences in the intent-to-treat analysis were accounted for by toxicity: 52.6% of subjects using HU experienced toxicity leading to discontinuation of randomized treatment versus 28.7% of subjects using no HU. CONCLUSION: The use of NVP in addition to a triple NRTI regimen improved both short- and long-term antiretroviral efficacy. The use of HU significantly contributed to treatment failure because of toxicity.

Adult↗
PubMed2000

Substitution of a nonnucleoside reverse transcriptase inhibitor for a protease inhibitor in the treatment of patients with undetectable plasma human immunodeficiency virus type 1 RNA.

Seventy-three patients infected with human immunodeficiency virus type 1 (HIV-1) were enrolled in a prospective observational study to investigate the efficacy and tolerance of substituting a nonnucleoside reverse transcriptase inhibitor (NNRTI) for a protease inhibitor (PI) in patients whose plasma viral load (pVL) was controlled by a PI regimen. After a median follow-up of 52 weeks, 63 patients (86.3%) had undetectable pVLs. The incidence of virological breakthrough at 12 months of follow-up was 6.5% (95% confidence interval [CI], 1-20) among patients who had been antiretroviral naive before receiving HAART and 19.2% (95% CI, 6-34) among patients who had been treated with antiretroviral drugs before receiving the PI regimen (P=.10).

CD4 Lymphocyte Count↗
PubMed2004

Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants.

Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.

Anti-HIV Agents↗
PubMedDate not supplied

Lactic acidosis associated with nucleoside reverse transcriptase inhibitors.

Limitations on antiretroviral therapies as a result of resistance and adverse events have been described in the literature. Lactic acidosis has been reported in patients on nucleoside reverse transcriptase inhibitors on rare occasions. Successful assessment and treatment of lactic acidosis is dependent on the nurse's role in the recognition of this condition. This article provides an overview of the clinical presentation, diagnosis, treatment strategies and nursing management of lactic acidosis in patients with HIV/AIDS.

Acidosis, Lactic↗
PubMed2006

Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.

Adult↗
PubMed2005

A prospective study of efficacy and safety of once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors in treatment-naive Thai patients.

OBJECTIVE: To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies. DESIGN: Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200-350 at screening were enrolled in this open-label 24week study. METHODS: Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities. RESULTS: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/microl and HIV RNA 50 118 (4.7 log10) copies/mi. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/microl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 (P = 0.957) or absolute HIV RNA at week 24 (P = 0.77). CONCLUSION: First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

Adult↗
PubMed2005

Quantitative structure-activity relationship analysis of pyridinone HIV-1 reverse transcriptase inhibitors using the k nearest neighbor method and QSAR-based database mining.

We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivity indices, which are derived from two-dimensional molecular topology. The modeling process entailed extensive validation including the randomization of the target property (Y-randomization) test and the division of the dataset into multiple training and test sets to establish the external predictive power of the training set models. QSAR models with high internal and external accuracy were generated, with leave-one-out cross-validated R2 (q2) values ranging between 0.5 and 0.8 for the training sets and R2 values exceeding 0.6 for the test sets. The best models with the highest internal and external predictive power were used to search the National Cancer Institute database. Derivatives of the pyrazolo[3,4-d]pyrimidine and phenothiazine type were identified as promising novel NNRTIs leads. Several candidates were docked into the binding pocket of nevirapine with the AutoDock (version 3.0) software. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitor nevirapine.

Database Management Systems↗
PubMed2002

Computer simulations of slow progression of human immunodeficiency virus infection and relapse during anti-HIV treatment with reverse transcriptase inhibitors and protease inhibitors.

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been very serious problems since the 1980s. The progression of HIV infection into AIDS can be suppressed to some extent with reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs); however, there are some serious problems with treatments using the anti-HIV drugs (e.g. very high expense, complicated administration, and drug resistance). Hence, more studies on HIV and the development of more effective anti-HIV treatments are required. We consider it important to understand the complex dynamics involved in HIV infection, and we therefore propose new mathematical models of HIV infection. In the modeling, we have paid attention to the nonlinear relations between stimuli and responses (i.e., when responses are plotted against the logarithm of stimuli, a sigmoid curve is obtained), and to lymphoid organs which seem more important than the blood compartment (i.e., lymphoid organs are major reservoirs of HIV virions and contain most of the lymphocytes). Using the models, we have found that viral antigenic mutation plays an important role in the slow progression in the chronic phase of HIV infection. We have also found that viral antigenic mutation can cause relapse of HIV infection when the inhibition rate of anti-HIV drugs is low and that viral antigenic mutation cannot cause relapse when the inhibition rate is high.

Antigenic Variation↗
PubMed1999

Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.

Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis.

Anti-HIV Agents↗
PubMed2006

Update on primary HIV-1 resistance in Argentina: emergence of mutations conferring high-level resistance to nonnucleoside reverse transcriptase inhibitors in drug-naive patients.

Here we present a survey including 52 drug-naive recently HIV-1-infected subjects from Buenos Aires City and province (79%) and 3 other regions in Argentina (21%). Recent infections were established from previous negative serology (32/52), indeterminate Western blot (12/52), or acute retroviral syndrome after high-risk HIV exposure (8/52) within 9 months before genotyping (median time, 4.2 months). Genotyping was performed from plasma by sequencing both protease and reverse transcriptase. Phylogenetic analysis combined with bootscanning resulted in 21 subtype B sequences and 31 B/F recombinants (RecBF). On protease, minor resistance-related mutations were found in both subtype B and RecBF with low frequencies. The substitution L89M, recently suggested as a resistance-related mutation in some subtype F viruses, was observed in 1 RecBF. On reverse transcriptase, major resistance-related mutations were found in 4 of 52 (7.7%) patients from different health centers: M41L (subtype B) and K103N+/-P225H (1 RecBF and 2 subtype B). The greater than 5% resistance threshold found indicates a need for sentinel resistance surveillances calling for an update in the current resistance testing guidelines in Argentina.

Argentina↗
PubMed2004

Prognostic factors in lactic acidosis syndrome caused by nucleoside reverse transcriptase inhibitors: report of eight cases and review of the literature.

We conducted a retrospective study to identify prognostic factors in the lactic acidosis syndrome (LAS) caused by nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/AIDS. Fifty-eight cases of LAS were included in our analysis, 8 from our hospital spanning the years 1992-2002, and 50 reported in the English language literature from 1986 through 2002. Peak venous lactate level was the best predictor of mortality. Zidovudine was associated with higher lactate levels and higher mortality than stavudine and lamuvidine. Mortality declined progressively after 1986 when the first cases of NRTI-related LAS were described. Increased mortality with zidovudine in this study appears due in part to its greater use prior to 1990 when LAS was not widely recognized as a potential complication of NRTI therapy.

Acidosis, Lactic↗
PubMed2005

Nonnucleoside HIV-1 reverse-transcriptase inhibitors, part 5. Synthesis and anti-HIV-1 activity of novel 6-naphthylthio HEPT analogues.

As part of a series of studies to discover new HIV reverse-transcriptase inhibitors, various novel 6alpha- and 6beta-naphthylthio 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (HEPT) derivatives were synthesized, and in vitro anti-HIV-1 activity was evaluated. The results revealed that most of 6alpha-naphthylthio HEPT derivatives (7a-w) showed good activity [for 7e, IC50 value of 0.048 microM and selectivity index (SI) value of 735; for 7h, IC50 value of 0.057 microM and SI value of 579; for 7k, IC50 value of 0.063 microM and SI value of 565], 6beta-naphthylthio HEPT derivatives (8a-f) showed low activity, but the introduction of alpha nitro group to the C-1 position of the 6beta-naphthyl ring in the 6beta-naphthylthio series (11a-c) resulted in a dramatic increase in anti-HIV-1 activity.

HIV Reverse Transcriptase↗
PubMedDate not supplied

Mechanisms of genotoxicity of nucleoside reverse transcriptase inhibitors.

Nucleoside analogs were first approved by the U.S. Food and Drug Administration for use against HIV-AIDS in 1987. Since then, these agents, now commonly referred to as nucleoside reverse transcriptase inhibitors (NRTIs), have become essential components of the Highly Active Antiretroviral Therapy (HAART) drug combinations used for treatment of Human Immunodeficiency Virus-1 (HIV-1) infections. Their antiretroviral activity is likely two-fold: incorporation of the drug into viral DNA and inhibition of the viral reverse transcriptase. However, incorporation of the drug into host nuclear and mitochondrial DNA may be largely responsible for dose-limiting toxicities. Azidothymidine (AZT, 3'-azido-3'-deoxythymidine, zidovudine), the first NRTI approved for the therapy of HIV-1, is incorporated into DNA, causes mutations in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) and thymidine kinase (TK) genes, and induces micronuclei, chromosomal aberrations, sister chromatid exchange, shortened telomeres, and other genotoxic effects in cultured cells. Genomic instability would be predicted as a consequence of these events. Metabolic pathways that result in the phosphorylation of AZT play a crucial role in AZT-DNA incorporation, and may be altered after prolonged treatment. For example, thymidine kinase 1, the enzyme responsible for AZT mono-phosphorylation, is down-regulated during long-term exposure and appears to be associated with AZT-induced replication inhibition and the accumulation of cells in S-phase. Detailed information on the mechanisms underlying NRTI-associated antiretroviral efficacy, toxicity, and metabolic resistance were not available when AZT was first approved for use as an antiretroviral agent. Current insights, based on 15 years of research, may lead to intervention strategies to attenuate toxicity without altering drug efficacy.

Animals↗
PubMed2002

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↗
PubMed2002

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↗
PubMed1999

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↗
PubMed1995

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↗