Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reverse Transcriptase Inhibitors”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 829 records · Page 46Linked to original sources
PubMed2002

Stampidine is a potent inhibitor of Zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical human immunodeficiency virus type 1 isolates with thymidine analog mutations.

We report the antiretroviral activity of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate) (stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, against primary clinical human immunodeficiency virus type 1 (HIV-1) isolates. STAMP inhibited each one of nine clinical HIV-1 isolates of non-B envelope subtype and 20 genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor-resistant HIV-1 isolates at subnanomolar to low-nanomolar concentrations.

Anti-HIV Agents↗
PubMed2002

Cutaneous manifestations of antiretroviral therapy.

The pandemic created by HIV, a retrovirus, has stimulated increased research in viral diseases and has generated greater interest in the development of antiretroviral medications. These new medications are presently divided into 3 categories: protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). These antiretroviral agents carry their own risk for causing adverse reactions, as well as drug interactions. The most recently approved class of antiretrovirals, PIs have been associated with lipodystrophy syndrome, hypersensitivity reactions, urticaria, morbilliform eruptions, and a large number of drug interactions. NNRTIs have resulted in various cutaneous eruptions, as well as a hypersensitivity syndrome. NRTIs have resulted in alterations of the nails, nail and mucocutaneous pigmentation, hair changes, vasculitis, and morbilliform eruptions. This article focuses on the cutaneous manifestations of antiretroviral therapy to help dermatologists recognize them.

Adult↗
PubMed2001

Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases.

OBJECTIVES: To compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: Data were analysed from three large HIV patient databases: Apache HIV Insight (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. RESULTS: The type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3--2.1 and relative hazard, 1.6; 95% confidence interval, 1.0--2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 x 10(9)cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. CONCLUSIONS: PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.

Adult↗
PubMed2003

Managing antiretroviral-associated liver disease.

The use of all potent drugs is associated with toxicities and antiretroviral (ARV) drugs are no exception. Antiretroviral therapy-associated hepatic toxicity is of increasing concern in the management of patients with HIV/AIDS. Liver toxicity has been reported in some HIV-infected patients being treated with drugs from all of these classes of ARV drugs: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although the majority of cases involve asymptomatic elevations of liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), severe, and, in a minority of cases, life threatening, liver disease has been reported in patients treated with ARV drugs. The exact causes of elevated plasma levels of AST and ALT are complex and, in many cases, obscure. The combination of viral hepatic disease, drugs that act adversely directly on the liver and drugs that act on other systems of the body which in turn, adversely affect the liver, can result in hepatic toxicity. Such toxicity may be inappropriately attributed solely to the direct effect of a drug. Knowledge of the possible causes of liver toxicity, and ways to avoid it, should reduce the risk of developing hepatotoxicity. The physician's task is to prevent the development of liver toxicity, e.g., by choosing appropriate therapeutic regimens and by careful management of the patient. This involves frequent monitoring of the patient, both clinically and by utilizing liver function tests on a regular basis. If signs and symptoms of liver disease do develop, prompt and expert management is essential. This review discusses the influence of a number of factors on hepatic toxicity including viral hepatitis, insulin resistance and the specific ARV drugs used in the treatment of patients with HIV/AIDS.

Chemical and Drug Induced Liver Injury↗
PubMed2002

DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants.

Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.

Animals↗
PubMed1992

Chemotherapeutic approaches to human immunodeficiency virus infections.

Since the discovery of human immunodeficiency virus (HIV) as the causative agent of acquired immune deficiency syndrome (AIDS), various attempts have been made to control this fatal disorder. In the replicative cycle of HIV, several steps have been identified as attractive targets for antiviral chemotherapy. Sulfated polysaccharides can block the virion binding to the CD4 receptor. 2',3'-Dideoxynucleosides including 3'-azido-3'-deoxythymidine (AZT) act as potent inhibitors of reverse transcriptase after intracellular phosphorylation. Only AZT and 2',3'-dideoxyinosine are available so far for the treatment of AIDS and AIDS-related complex. Non-nucleoside reverse transcriptase inhibitors of HIV-1 and viral protease inhibitors are the new classes of compounds that are now extensively studied. These compounds may add a new dimension to the prospects of anti-AIDS chemotherapy.

Antiviral Agents↗
PubMed2006

New antiretroviral drugs.

Despite the availability of 21 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens remain hampered by issues of toxicity, convenience, cost, incomplete viral suppression, and drug resistance. Expansion of the currently available therapeutic options through the reformulation of available agents, discovery of new compounds with antiretroviral activity, and the exploitation of novel drug targets are critical. This review describes the status of new nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. We also summarize new classes of antiretroviral therapy in clinical development including the attachment inhibitors, chemokine receptor antagonists, integrase inhibitors, and maturation inhibitors.

Anti-HIV Agents↗
PubMed2001

[HIV-1 therapy in the Netherlands; virological and immunological response to antiretroviral therapy].

OBJECTIVE: To evaluate the effect of treatment of HIV-1 infection with combination therapy consisting of since 1996 in the Netherlands available protease and reverse transcriptase inhibitors. DESIGN: Prospective cohort study. METHODS: In an observational clinical cohort of HIV-1-infected individuals, the short-term successful treatment end point of antiviral therapy including at least one antiretroviral drug licensed in the Netherlands since July 1, 1996 (protease inhibitors and reverse transcriptase inhibitors), was HIV-1 RNA plasma levels < or = 500 copies/ml (virological success). Cox proportional hazard models were used to identify prognostic markers for therapy success. The study included 2,148 infected individuals with a median follow-up of 135 weeks of treatment; 1,049 had been pre-treated with antiretroviral drugs before starting their new regimen and 1,099 were treatment naive. RESULTS: Plasma HIV-1 RNA levels < or = 500 copies/ml at 24 weeks of treatment were seen in 61% of all patients. The chance of therapy success for naive patients was twice that for pre-treated patients (relative risk: 1.8; p < or = 0.001). Following the first 24 weeks, the chance of virological success was higher in the naive group (78% versus 63%; p < or = 0.001), and the number of naive patients failing therapy after initial success was smaller compared to pre-treated patients (22% versus 45%; p < or = 0.001). In the naive group, the CD4+ T-cell number increased from 239 to 440 (x 10(6) cells/l) in case of success, and decreased from 150 to 320 in case of treatment failure. HIV-1 related morbidity declined from 0.26 to 0.05 and mortality dropped from 0.07 to 0.03 per person-year of follow-up. Regimens were changed at least once in 76% of patients. Toxicity and therapy failure were the main reasons for regimen changes in naive and pre-treated patients, respectively. CONCLUSION: A combination of antiretroviral drugs, including at least one of the drugs licensed since 1996, led to a drop in HIV-1 plasma concentrations. Morbidity and mortality also decreased. The chance of a better immunological and virological response to the new drug regimens was greatest in therapy-naive patients.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virus-infected liver and kidney transplant recipients.

BACKGROUND: With advances in antiretroviral therapy, many human immunodeficiency virus (HIV)-infected individuals are living longer and developing end-stage renal or hepatic disease requiring transplantation. Maintaining the viability of the transplant and suppressing HIV replication requires concomitant use of immunosuppressants (e.g., cyclosporine) and antiretrovirals (e.g., protease inhibitors or nonnucleoside reverse transcriptase inhibitors), which leads to drug interactions. To assist in appropriate clinical management of HIV-infected transplant recipients, the authors describe the pharmacokinetic interactions between cyclosporine and the antiretroviral medications, and required modifications of cyclosporine dosing. METHODS: Eighteen HIV-infected subjects with end-stage kidney or liver disease underwent transplantation. Subjects had pharmacokinetic studies before transplantation and for up to 2 years posttransplantation (at weeks 2-4, 12, 28, 52, and 104). Protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and cyclosporine concentrations were measured by liquid chromatography-mass spectrometry in plasma and whole blood, respectively. RESULTS: Subjects using protease inhibitors and cyclosporine had a threefold increase in cyclosporine area under the curve (4,190+/-2,180-11,900+/-1,600 ng*hr/mL, P<0.01), necessitating an 85% reduction in cyclosporine dose over a 2-year period (1.3+/-1.5-0.2+/-0.0 mg/kg/dose), leading to a progressive increase in oral cyclosporine bioavailability (R=0.92, P<0.02). Subjects on nonnucleoside reverse-transcriptase inhibitors showed minimal interactions with cyclosporine, and subjects on both HIV treatments had intermediate responses. CONCLUSIONS: HIV-infected transplant recipients on protease inhibitors require markedly lower doses of cyclosporine, with continued lowering of the cyclosporine dose over time and ongoing cyclosporine trough monitoring because of progressively increasing cyclosporine bioavailability. Medication changes must be carefully managed to avoid insufficient immunosuppression or toxicity resulting from drug interactions.

Adolescent↗
PubMed2003

HIV viral suppression in the era of antiretroviral therapy.

Altogether 42 million people worldwide have been infected with HIV, and 12 million have died over the last 20 years. Effective antiretroviral therapy has lead to sustained HIV viral suppression and immunological recovery in patients who have been infected with the virus. The incidence of AIDS has declined in the Western world with the introduction of effective antiretroviral therapy. Questions on When to start treatment?, What to start with?, How to monitor patients?, remain heavily debated. Adherence to antiretroviral treatment remains the cornerstone of effective treatment, and failure to adhere is the strongest predictor of virological failure. Long term therapy can lead to metabolic complications. Resource poor countries are dealing with difficult issues such as mother to child prevention of HIV transmission. Other treatment options are now available, with the recent introduction of fusion inhibitors, second generation non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors to clinical practice.

Anti-HIV Agents↗
PubMedDate not supplied

Antiretrovirals, part 1: overview, history, and focus on protease inhibitors.

This column is the first in a series on HIV/AIDS antiretroviral drugs. This first review summarizes the history of HIV/AIDS and the development of highly active antiretroviral therapy (HAART) and highlights why it is important for non-HIV specialists to know about these drugs. There are four broad classes of HIV medications used in varying combinations in HAART: the protease inhibitors, nucleoside analogue reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, and cell membrane fusion inhibitors. This paper reviews the mechanism of action, side effects, toxicities, and drug interactions of the protease inhibitors.

Acquired Immunodeficiency Syndrome↗
PubMed2001

New Drugs for the Treatment of HIV Infection.

Despite the availability of 15 approved drugs for the treatment of HIV infection, issues of convenience, tolerability, and antiretroviral activity make the continued development of newer drugs important. New drugs in clinical development represent both existing classes of antiretroviral agents--reverse transcriptase inhibitors (eg, diaminopurine dioxolane), nonnucleoside reverse transcriptase inhibitors (eg, capravirine), and protease inhibitors (eg, tipranavir and BMS-232632)--and newer classes of antiretroviral agents, such as nucleotide analogue reverse transcriptase inhibitors (eg, tenofovir) and fusion inhibitors (eg, pentafuside). Newer drugs may offer improvements over existing agents by having simpler dosing schedules (once or twice daily), better tolerability, or improved virologic activity against wild-type or resistant virus. Continued advancements in HIV treatment will stem from ongoing development of antiretroviral drugs.

Journal Article↗
PubMed2004

Treatment interruption for virological failure or as sparing regimen in children with chronic HIV-1 infection.

OBJECTIVE: To assess both benefits and risks related to treatment interruption (TI) in children with chronic HIV-1 materno-fetal infection. DESIGN: : A multicentre, retrospective analysis in five university hospital pediatric departments in France. METHODS: Clinical events, plasma HIV-1 RNA, CD4 cell counts, CD4 percentages (CD4%) and genotypes were recorded in 24 patients before and during TI. Patients were classified as sparing regimen or virological failure groups according to the main reason for treatment interruption. Clinical events, immuno-virological evolution and genotype reversions were monitored. RESULTS: After a median of 40 weeks of TI, none of the patients presented with an AIDS-defining event. For the whole cohort, median viral load variation from baseline, measured during TI was +1.26 log10 copies/ml (range, -0.22, +4.3 log10) with large inter-individual variability, median absolute CD4 cell loss was 32.5% (range, -82, +17%). These variations were not different in the two patient groups. The mean number of mutations conferring resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors at baseline and last evaluation did not differ significantly. Few mutation reversions to wild type were noted in our cohort. CONCLUSIONS: Treatment interruption in children with chronic HIV-1 infection is associated with higher viral load increases than observed in adult patients. The CD4 cell loss is comparable. Although no clinical AIDS-defining event was noted close monitoring is required when TI is proposed to HIV-infected children. Very few reversion mutations were observed during treatment interruption.

Adolescent↗
PubMedDate not supplied

Comparative study of non nucleoside inhibitors with HIV-1 reverse transcriptase based on 3D-QSAR and docking.

The intermolecular interaction between two types of non nucleoside reverse transcriptase inhibitors (NNRTIs), HEPT and TIBO, and HIV reverse transcriptase receptor (HIVRT) was investigated. The result of docking study showed that two types of NNRTIs presented similar interaction mechanism with HIVRT. The most active compound of every type of inhibitors could form one hydrogen bond with the residue Lys101 and has hydrophobic interaction with residues Tyr181, Tyr188 and Tyr318, etc. Three 3D-QSAR models including two partial correlation models (one for each family of HEPT and TIBO) and a mixed model gathering two families were constructed. Comparative study of these models indicated that the mixed model offered the strongest prediction ability. For this model, the cross-validated q2 values were 0.720 and 0.675, non-cross-validated r2 values were 0.940 and 0.920 for CoMFA and CoMSIA, respectively. It has been validated by using a test set of 27 inhibitors. Compared with previously reported works, our model showed better prediction ability. It could help us to insight the interaction between NNRTIs and HIVRT, and to design new anti-HIV NNRTIs inhibitors.

Drug Interactions↗
PubMed2007

Time trends for HIV-1 antiretroviral resistance among antiretroviral-experienced and naive pregnant women in New York City during 1991 to early 2001.

Time trends in the prevalence of drug resistance to antiretroviral therapy (ART) in pregnant women have not been studied. Treatment and prophylactic efficacy could be compromised by drug-resistant HIV strains. We conducted a repeated cross-sectional study of antiretroviral resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and of major mutations to protease inhibitors (PIs) in virus isolates from 300 HIV-infected pregnant women in New York City from 1991 to early 2001. The overall prevalence of mutations for NRTIs from 1991 to early 2001 was higher for ART-experienced (25.6% [95% confidence interval (CI): 19.1% to 32.1%]) than ART-naive (8.6% [95% CI: 3.7% to 13.4%]) mothers (P < 0.002). For NNRTIs, the overall prevalence of mutations was somewhat higher among ART-experienced (5.8% [95% CI: 2.3% to 9.3%]) versus ART-naive (1.6% [95% CI: 0% to 3.7%]) women (P = 0.06), and increased over time for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-19.4%; P = 0.0002). The prevalence of PI-associated mutations was also higher overall among ART-experienced mothers (5.8% [95% CI: 2.3% to 9.3%] vs. 1.6% [95% CI: 0% to 3.7%]; P = 0.06), with increases over time seen for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-16.1%; P = 0.0008). The increasing prevalence of drug resistance in pregnant women, including those who are drug-naive, underscores the necessity for resistance testing to guide treatment to achieve suppression of the mother's virus.

Adult↗
PubMed2000

Inhibitory effect of human immunodeficiency virus protease inhibitors on multidrug resistance transporter P-glycoproteins.

The objective of this study was to determine whether human immunodeficiency virus (HIV) protease inhibitors (saquinavir, ritonavir and nelfinavir) interact with other HIV protease inhibitors and/or HIV reverse transcriptase inhibitors (zidovudine, didanosine, lamivudine, zalcitabine and sanilvudine). We measured transport of nelfinavir, an HIV protease inhibitor which is known as a substrate for the multidrug resistance transporter P-glycoprotein (P-gp), in an epithelial monolayer model and Ki for P-gp of some drugs by a calcein flux assay. Transport in a basal to apical direction was 2-fold greater than apical to basal flux for nelfinavir, Ki for P-gp of a potent P-gp inhibitor cyclosporin A was 1.09 microM and those of ritonavir and nelfinavir were 111 microM and 28.6 microM, whereas all HIV reverse transcriptase inhibitors gave high K1 values. These data show that nelfinavir, which is a substrate for P-gp, inhibits a P-gp function as a drug efflux pump and that HIV reverse transcriptase inhibitors do not inhibit P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Amprenavir: new preparation. Another HIV protease inhibitor: no proven advance.

(1) The reference antiretroviral treatment for HIV-infected patients is a three-drug regimen combining drugs from different families, namely two nucleoside reverse transcriptase inhibitors + a protease inhibitor or a non nucleoside reverse transcriptase inhibitor. In our opinion, indinavir is the first-choice protease inhibitor. (2) The clinical file on amprenavir is limited. In particular, it is not known whether the recommended dose regimen (1 200 mg twice a day) is the best one. A 48-week trial involving 232 patients previously untreated with antiretrovirals showed that the combination of amprenavir (1 200 mg) + lamivudine (150 mg) + zidovudine (300 mg), administered twice a day, was more effective than lamivudine + zidovudine on viral load. (3) An unblinded trial involving 504 patients, who had already received a reverse transcriptase inhibitor but no protease inhibitor, compared three-drug regimens consisting of amprenavir (1 200 mg twice a day) and two reverse transcriptase inhibitors, or indinavir (800 mg three times a day) and two reverse transcriptase inhibitors, for 48 weeks. Changes in viral load and the CD4+ lymphocyte count did not favour the amprenavir-containing regimen. (4) Laboratory studies suggest that the risk of cross-resistance between amprenavir and other HIV protease inhibitors is lower than with other compounds of this class. However, it is unclear whether this means that amprenavir would be clinically effective after failure of one or several other protease inhibitors. (5) The main adverse effects of amprenavir are gastrointestinal disorders and paraesthesias. Overall, the safety profile resembles that of the other protease inhibitors. (6) Like other protease inhibitors, amprenavir can potentially interact with many other drugs, owing to its hepatic metabolism. (7) Amprenavir is taken in two daily doses irrespective of meal times, but this advantage over other protease inhibitors is cancelled out by the fact that patients have to swallow 8 large soft capsules at each intake. (8) In our opinion, pending further data, amprenavir should be used only in well-conducted clinical trials.

Anti-Infective Agents↗