PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Reverse Transcriptase Inhibitors”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2003

Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy.

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy provides sufficient conditions for progressive subcutaneous fat wasting in HIV-infected patients. As NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion, determinants of cellular mtDNA copy number and mitochondrial mass in adipocyte samples from NRTI-treated HIV-infected patients and antiretroviral-naive controls were investigated. Adipose tissue morphology was also assessed. METHODS: Subcutaneous fat samples were obtained from NRTI-treated, HIV-infected patients (n = 21), antiretroviral therapy-naive HIV-infected controls (n = 11), and HIV-seronegative controls (n = 6). Non-adipocytes were removed by collagenase digestion. Adipocyte mtDNA copies/cell was measured using a real time PCR-based assay, and adipocyte mitochondrial protein content was also measured. Light and electron microscopy were performed on tissue samples. FINDINGS: Adipocyte mtDNA copies/cell values were similar (P = 0.56) in HIV seronegative and HIV-infected control groups. NRTI treatment was associated with reduced adipocyte mtDNA copies/cell, representing mean mtDNA depletion in NRTI-treated individuals of 77.7% compared with the mean value for the HIV-infected control group (P < 0001). Additionally, significant differences were found in adipocyte mtDNA copies/cell between patients receiving stavudine (n = 12, mean mtDNA depletion 87.1%) and zidovudine (n = 9, mean mtDNA depletion 52.1%) (P < 0.001). Adipocyte mitochondrial mass was increased in the stavudine group only (mean increase 289%, P < 0.01). INTERPRETATION: NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting. Morphologic assessment also supports a role for NRTI therapy in inducing adipocyte metabolic dysfunction and cell death.

Adipocytes↗
PubMed2002

ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse transcriptase.

Removal of nucleoside chain terminator inhibitors mediated by human immunodeficiency virus (HIV) reverse transcriptase (RT) using ATP as an acceptor molecule has been proposed as a novel mechanism of HIV resistance. Recombinant wild-type and mutant HIV type 1 (HIV-1) RT enzymes with thymidine analog resistance mutations D67N, K70R, and T215Y were analyzed for their ability to remove eight nucleoside reverse transcriptase inhibitors in the presence of physiological concentrations of ATP. The order for the rate of removal of the eight inhibitors by the mutant RT enzyme was zidovudine (AZT) > stavudine (d4T) >> zalcitabine (ddC) > abacavir > amdoxovir (DAPD) > lamivudine (3TC) > didanosine (ddI) > tenofovir. Thymidine analogs AZT and d4T were the most significantly removed by the mutant enzyme, suggesting that removal of these inhibitors by the ATP-dependent removal mechanism contributes to the AZT and d4T resistance observed in patients with HIV expressing thymidine analog resistance mutations. ATP-dependent removal of tenofovir was 22- to 35-fold less efficient than removal of d4T and AZT, respectively. The addition of ATP and the next complementary deoxynucleoside triphosphate caused a reduction of ATP-mediated removal of d4T, ddC, and DAPD, while AZT and abacavir removal was unaffected. The reduction of d4T, ddC, and DAPD removal in the presence of the deoxynucleoside triphosphate could explain the minor changes in susceptibility to these drugs observed in conventional in vitro phenotypic assays using cells that have higher deoxynucleoside triphosphate pools. The minimal removal of abacavir, ddC, DAPD, 3TC, ddI, and tenofovir is consistent with the minor changes in susceptibility to these drugs observed for HIV mutants with thymidine analog resistance mutations.

Adenine↗
PubMedDate not supplied

Efficacy and safety of abacavir plus lamivudine versus didanosine plus stavudine when combined with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor, or both in HIV-1 positive antiretroviral-naive persons.

PURPOSE: The combination of abacavir + lamivudine (ABC+3TC) versus didanosine + stavudine (ddI+d4T), each combined with other classes of antiretrovirals (ARVs) in ARV-naive patients, was compared for the combined endpoint of time to plasma HIV RNA >50 copies/mL (at or after the 8-month visit) or death (primary endpoint) in a nested substudy of an ongoing multicenter randomized trial. METHOD: The substudy enrolled 182 patients; mean HIV RNA and CD4+ cell counts at baseline were 5.1 log10 copies/mL and 212 cells/mm3, respectively. RESULTS: After a median follow-up of 28 months, rates of primary endpoint were 57.2 and 67.8 per 100 person-years for the ABC+3TC and ddI+d4T groups (hazard ratio [HR]=0.81, 95% confidence interval [CI] 0.58-1.14, p=.23). CONCLUSION: There was a trend for treatments containing ABC+3TC to be better than treatments containing ddI+d4T with respect to HIV RNA decreases, CD4+ cell count increases, and tolerability.

Anti-HIV Agents↗
PubMed2004

Protease inhibitor and nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected women.

The pharmacokinetics of antiretrovirals (ARVs) in the female genital tract (FGT) are likely to influence vertical and sexual transmission of HIV, the development of viral resistance, and post-exposure prophylaxis regimens. This study is the first to compare ARV concentrations in direct aspirates of cervicovaginal fluid (CVF) and blood plasma (BP). This unique method provides direct assessment of concentrations without the confounding of cervicovaginal lavage dilution. Of 8 ARVs, CVF concentrations ranged from <10% to >100% of BP concentrations. These large differences in CVF penetration suggest that further research into ARV pharmacokinetics and drug efficacy in the FGT is necessary.

Adult↗
PubMed2002

Differences in cellular activation and apoptosis in HIV-infected patients receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors.

The mechanism of CD4(+) T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8(+) T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+) and CD8(+) lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8(+) T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4(+) counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.

Anti-HIV Agents↗
PubMed2005

Superiority of protease inhibitors over nonnucleoside reverse-transcriptase inhibitors when highly active antiretroviral therapy is resumed after treatment interruption.

Forty-five human immunodeficiency virus (HIV)-infected patients stopped taking treatment but resumed taking it thereafter. All 11 who resumed treatment with their prior protease inhibitor (PI)-based regimen reattained an undetectable virus load, whereas this occurred for only 15 (44%) of 34 patients who resumed nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based treatment (P<.001). Distinct pharmacokinetics and resistance barriers may result in different performances for PIs and NNRTIs after treatment interruptions.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Simultaneous separation of 11 protease and reverse transcriptase inhibitors for human immunodeficiency virus therapy by co-electroosmotic capillary zone electrophoresis.

In the present investigation, a co-electroosmotic capillary zone electrophoretic method is shown for the simultaneous separation of protease inhibitors and reverse transcriptase inhibitors, which are used as antiretroviral therapy drags against the human immunodeficiency virus (HIV). The investigated drugs carry basic amino groups, thus the electrophoretic system takes advantage of an acidic buffer electrolyte. In order to establish a strong cathodic electroosmotic flow (EOF), a poly-anionic surfactant is added to the background electrolyte. Thus, fast migration times due to a co-directional migration of analytes and EOF (co-electroosmotic CE) are obtained. The developed separation system exhibits good selectivities for the investigated compounds and sufficient sensitivity to monitor drug levels in the low ppm range in HIV positive patients who are treated by highly active anitiretroviral therapy.

Electrophoresis, Capillary↗
PubMed2000

[Non-nucleoside reverse transcriptase inhibitors].

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz; other compounds are under evaluation. NNRTIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions with compounds utilizing the same metabolic pathway, particularly PIs, whose plasma levels are altered in the presence of NNRTIs. NNRTIs are drugs with a low genetic barrier, i.e. a single mutation in RT genoma induces a high-level of phenotypic resistance, preventing the use of NNRTIs as monotherapy. In naive patients, several trials have shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as second-line therapy. However, due to the rapid emergence of resistant virus to these compounds in case of incomplete viral suppression, NNRTIs should not be added to current failing antiretroviral regimen. The most common side-effect reported with nevirapine and delavirdine is rash. The incidence of rash is rather similar under these two compounds, but severe rash is less frequent with delavirdine. The most common adverse reactions reported with efavirenz are central nervous system complaints such as dizziness. Rash is reported less frequently than with nevirapine or delavirdine, and is usually mild. NNRTIs resistance mutations are located in the amino acid residues aligning the NNRTI-binding "pocket" site. High-level resistance is often associated with a single point mutation which develops within this site (especially codon groups 100 - 108 and 181 - 190). Patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations. NNRTIs should always be used as part of a potent antiretroviral therapy to insure suppression of viral replication, thus circumventing the rapid selection of cross-resistant variants.

Anti-HIV Agents↗
PubMedDate not supplied

Clinical implications of HIV drug resistance to nucleoside and nucleotide reverse transcriptase inhibitors.

This review focuses on issues pertinent to the epidemiology and clinical interpretation of resistance to nucleos(t)ide reverse transcriptase inhibitors. Nucleoside reverse transcriptase inhibitor resistance mutations, and especially thymidine analog mutations, remain the most common form of resistance detected in drug-naive patients. At the same time, improved treatment strategies, changes in prescribing policies, and prompt management of treatment failure are changing the prevalence and patterns of nucleoside reverse transcriptase inhibitor resistance in treatment-experienced patients. The clinical interpretation of nucleoside reverse transcriptase inhibitor resistance is being increasingly refined, helped by improved understanding of resistance pathways, development of sophisticated methods of analysis of genotypic resistance patterns, and introduction of clinically relevant cutoffs. Correlation of genotypic and phenotypic resistance data to clinical outcomes is essential to allow appropriate interpretation. In some cases, phenotypic data, either obtained directly by phenotypic tests or extrapolated from genotypic results, provide the most immediate predictors of virologic response. In other cases, genotypic analyses identify mutations that impact on responses without showing a marked effect on the phenotype, by either acting as "sentinel" markers for the presence of resistance undetectable by standard methods, or by lowering the genetic barrier to the evolution of resistance. The potential benefits of nucleoside reverse transcriptase inhibitor resistance, through hypersusceptibility and fitness effects, are also increasingly understood and exploited in clinical practice. Although progress has been significant, there remain many challenges. It is often questioned whether genotypic scores and clinical cutoffs obtained by various methods and from frequently small datasets can be reliably extrapolated to the general population of treated patients. At the same time, there is a need to define the role of reverse transcriptase mutations that are identified by statistical analyses as being associated with nucleoside reverse transcriptase inhibitor exposure, but have unknown effects on virus phenotype and clinical outcome. Novel mechanisms have also been proposed to play a role in nucleoside reverse transcriptase inhibitor resistance, including changes in RNaseH that are not targeted by routine testing at present. One additional, currently unresolved issue is the clinical relevance of minority resistant species and the feasibility of introducing ultra-sensitive resistance tests in routine diagnostic settings. The most appropriate viral-load cutoff for performing resistance tests and the reliability of results obtained at low copy numbers are similarly controversial. In spite of these limitations, resistance testing with appropriate interpretation provides an important guide to successful treatment outcomes and necessary support to the introduction of new treatment strategies.

Drug Resistance, Multiple, Viral↗
PubMed2004

Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials.

OBJECTIVE: To compare the clinical efficacy of triple antiretroviral regimens based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) in adults positive for antibodies to HIV-1. DESIGN: Systematic review and meta-analysis using indirect comparisons of clinical trials comparing three drug regimens based on two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or an NNRTI with two drug regimens (two NRTIs). Participants had no previous exposure to protease inhibitors or NNRTIs. DATA SOURCES: Medline, the Cochrane controlled trials register, Aidstrials, Aidsdrugs, conference proceedings, and trial registers. MAIN OUTCOME MEASURE: Progression to AIDS or death. RESULTS: 14 trials, totalling 6785 patients, were identified. Most patients had been exposed to an NRTI and had advanced immunodeficiency at baseline; 1096 progressed to AIDS or died. Seven trials assessed protease inhibitors based triple regimens and seven assessed NNRTI based triple regimens (nevirapine or delavirdine). Triple therapy was more effective than dual therapy. The effect was pronounced for protease inhibitor based regimens (odds ratio 0.49, 95% confidence interval 0.41 to 0.58) but non-significant for NNRTI based regimens (0.90, 0.71 to 1.15). Indirect comparison of the two regimens gave an odds ratio of 0.54 (0.49 to 0.73) in favour of protease inhibitor based treatments. Increases in CD4 cell counts were smaller and suppression of viral replication less with NNRTI based regimens. CONCLUSIONS: Indirect evidence shows that protease inhibitor based triple regimens are superior to regimens based on the NNRTIs nevirapine and delavirdine in patients with advanced immunodeficiency who have been exposed to NRTIs. Large trials with clinical end points are required.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Effects on immunological and virological outcome of patients using one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor in a triple antiretroviral therapy: normal clinical practice versus clinical trial findings.

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Adult↗
PubMed2005

Simple and simultaneous determination of the hiv-protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir plus M8 nelfinavir metabolite and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine in human plasma by reversed-phase liquid chromatography.

Several studies suggest that therapeutic drug monitoring of protease inhibitors and nonnucleoside reverse transcriptase inhibitors may contribute to the clinical outcome of HIV-infected patients. Because of the growing number of antiretroviral drugs and of drug combinations than can be administered to these patients, an accurate high-performance liquid chromatographic (HPLC) method allowing the simultaneous determination of these drugs may be useful. To date, the authors present the first simultaneous HPLC determination of the new protease inhibitor atazanavir with all the others currently in use (M8 nelfinavir metabolite included) and the 2 widely used nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. This simple HPLC method allows the analysis all these drugs at a single ultraviolet wavelength following a 1-step liquid-liquid extraction procedure. A 500-muL plasma sample was spiked with internal standard and subjected to liquid-liquid extraction using by diethyl ether at pH 10. HPLC was performed using a Symmetry Shield RP18 and gradient elution. All the drugs of interest and internal standard were detected with ultraviolet detection at 210 nm. Calibration curves were linear in the range 50-10,000 ng/mL. The observed concentrations of the quality controls at plasma concentrations ranging from 50 to 5000 ng/mL for these drugs showed that the overall accuracy varied from 92% to 104% and 92% to 106% for intraday and day-to-day analysis, respectively. No metabolites of the assayed compounds or other drugs commonly coadministered to HIV-positive patients were found to coelute with the drugs of interest or with the internal standard. This assay was developed for the purpose of therapeutic monitoring (TDM) in HIV-infected patients.

Alkynes↗
PubMed2004

High-performance liquid chromatography assay for the quantification of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in human plasma.

An accurate, sensitive, and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of HIV-protease inhibitors (PIs) (indinavir, IDV; amprenavir, APV; saquinavir, SQV; nelfinavir, NFV; ritonavir, RTV; and lopinavir, LPV) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, NVP; delavirdine, DLV; and efavirenz, EFV) in human blood plasma is described. The method provides excellent resolution and peak shape for nine analytes through a linear gradient (36-86%) of 25% phosphate buffer (pH 4.5), 60% acetonitrile, 15% methanol, and 0.75 ml TFA, with a gradient mobile phase flow rate (0.9-1.1 ml) over 30 min run time. The optimized solid phase extraction (SPE) extraction method using (1.0 ml, 100mg BOND ELUT-C18 Varian) column provides a clean base line and high extraction efficiency using a 550 microl plasma sample. The method was validated over the range of 10-10,000 ng/ml for NVP, IDV, and SQV; 10-5000 ng/ml for EFV; 25-10000 ng/ml for APV; and 25-5000 ng/ml for DLV, NFV, RTV, and LPV. This method is accurate (average accuracies of three different concentrations ranged from 91 to 112%), and precise (within- and between-day precision measures ranged from 0.2 to 5.7% and 0.1 to 5.4%, respectively). This method is suitable for use in clinical pharmacokinetic studies as well as in therapeutic drug monitoring (TDM).

Chromatography, High Pressure Liquid↗
PubMed2001

Use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors among Medicaid beneficiaries with AIDS.

OBJECTIVES: This study compared the use of new antiretroviral treatments across sociodemographic subgroups during the 3 years after the introduction of these treatments and examined diffusion of the therapies over time. METHODS: Merged surveillance and claims data were used to examine use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (PI/NNRTIs) among New Jersey Medicaid beneficiaries with AIDS. RESULTS: In 1996, there were sharp disparities in use of PI/NNRTI therapy among racial minorities and injection drug users, even after control for other patient characteristics. These gaps had decreased by 1998. Higher PI/NNRTI treatment rates were also observed among beneficiaries enrolled in a statewide HIV/AIDS-specific home- and community-based Medicaid waiver program. CONCLUSIONS: Even within a population of individuals similar in regard to health coverage, there were substantial sociodemographic differences in use of PI/NNRTIs during the early years after their introduction. These differences narrowed as new treatments became standard. Participation in a case-managed Medicaid waiver program seems to be associated with a more appropriate pattern of use. These results suggest a need to address nonfinancial barriers to care.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Mutational analysis of Tyr-318 within the non-nucleoside reverse transcriptase inhibitor binding pocket of human immunodeficiency virus type I reverse transcriptase.

The highly conserved Tyr-318 is part of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-specific lipophilic pocket of human immunodeficiency virus type I reverse transcriptase (RT) and makes contact within 4 A with the NNRTIs in all reported RT/NNRTI complexes. Using site-directed mutagenesis, six mutant RTs were constructed bearing the mutations Y318H, Y318K, Y318L, Y318C, Y318W, and Y318F. We found that only the Y318W and Y318F mutant RTs retained substantial RT activity, whereas the catalytic activities of the Y318K, Y318C, Y318H, and Y318L RT mutants were less than 5% of the wild-type activity. The Y318F mutant RT retained substantial sensitivity to the majority of NNRTIs tested, whereas the Y318W mutant RT showed varying degrees of resistance to NNRTIs. Subunit-specific site-directed mutagenesis revealed that there was no difference in the catalytic activity or resistance/sensitivity spectrum toward NNRTIs regardless of whether the Tyr-318 mutation was introduced in both subunits or only in the p66 subunit of RT. Recombinant viruses harboring the Y318F or Y318W mutation in the RT showed a similar resistance/sensitivity pattern to NNRTIs as their corresponding 318 mutant recombinant RTs. Our findings stress a functional or structural role for Tyr-318 in wild-type RT and argue for the design of novel NNRTIs that interact more closely with this amino acid in the NNRTI-specific pocket of human immunodeficiency virus type I RT.

Amino Acid Substitution↗
PubMed2002

High-performance liquid chromatographic method for the simultaneous determination of the six HIV-protease inhibitors and two non-nucleoside reverse transcriptase inhibitors in human plasma.

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Alkynes↗
PubMedDate not supplied

Clinical uses of non-nucleoside reverse transcriptase inhibitors.

Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV-1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first-line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI-based regimens over 1-2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such 'switch' strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI-associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI-based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV-1 transmission with a simple, cost-effective regimen.

Alkynes↗