scholarly journals The Need for Development of New HIV-1 Reverse Transcriptase and Integrase Inhibitors in the Aftermath of Antiviral Drug Resistance

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Mark A. Wainberg
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Antiviral Drug ◽  
Antiviral Resistance ◽  
Strand Transfer ◽  
Reverse Transcriptase Inhibitors ◽  
Major Step ◽  
Genetic Barrier ◽  
Highly Active

The use of highly active antiretroviral therapy (HAART) involves combinations of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. There are two broad classes of reverse transcriptase inhibitors, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first classes of such compounds were developed, viral resistance against them has necessitated the continuous development of novel compounds within each class. This paper considers the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second line therapy and describes the patterns of resistance associated with their use, as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with low genetic barrier are more commonly used in resource-limited settings. Their use results to the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings. More recently, the advent of integrase strand transfer inhibitors represents another major step forward toward control of HIV infection, but these compounds are also susceptible to problems of HIV drug resistance.

scholarly journals Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors

2012 ◽  
Vol 56 (10) ◽  
pp. 5000-5008 ◽  
Author(s):  
Eugene L. Asahchop ◽  
Mark A. Wainberg ◽  
Richard D. Sloan ◽  
Cécile L. Tremblay
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Antiviral Drug ◽  
Transcriptase Inhibitor ◽  
Antiviral Resistance ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Genetic Barrier ◽  
Highly Active ◽  
Underlying Mechanisms

ABSTRACTHighly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

scholarly journals DPC 817: a Cytidine Nucleoside Analog with Activity against Zidovudine- and Lamivudine-Resistant Viral Variants

2002 ◽  
Vol 46 (5) ◽  
pp. 1394-1401 ◽  
Author(s):  
Raymond F. Schinazi ◽  
John Mellors ◽  
Holly Bazmi ◽  
Sharon Diamond ◽  
Sena Garber ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Half Life ◽  
Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Plasma Half Life

ABSTRACT 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.

scholarly journals Analysis of HIV- type 1 protease and reverse transcriptase in Brazilian children failing highly active antiretroviral therapy (HAART)

2005 ◽  
Vol 47 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Daisy Maria Machado ◽  
Silvana Cláudia Fernandes ◽  
Regina Célia de Menezes Succi ◽  
Wilton Santos Freire ◽  
Cláudio Sérgio Pannuti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Genotypic Resistance ◽  
Highly Active ◽  
Drug Classes ◽  
Antiretroviral Drug ◽  
Genotypic Analysis

The aim of this study was to evaluate the genotypic resistance profiles of HIV-1 in children failing highly active antiretroviral therapy (HAART). Forty-one children (median age = 67 months) receiving HAART were submitted to genotypic testing when virological failure was detected. cDNA was extracted from PBMCs and amplified by nested PCR for the reverse transcriptase and protease regions of the pol gene. Drug resistance genotypes were determined from DNA sequencing. According to the genotypic analysis, 12/36 (33.3%) and 6/36 (16.6%) children showed resistance and possible resistance, respectively, to ZDV; 5/36 (14%) and 4/36 (11.1%), respectively, showed resistance and possible resistance to ddI; 4/36 (11.1%) showed resistance to 3TC and D4T; and 3/36 (8.3%) showed resistance to Abacavir. A high percentage (54%) of children exhibited mutations conferring resistance to NNRTI class drugs. Respective rates of resistance and possible resistance to PIs were: RTV (12.2%, 7.3%); APV (2.4%, 12.1%); SQV(0%, 12.1%); IDV (14.6%, 4.9%), NFV (22%, 4.9%), LPV/RTV (2.4%, 12.1%). Overall, 37/41 (90%) children exhibited virus with mutations related to drug resistance, while 9% exhibited resistance to all three antiretroviral drug classes.

scholarly journals The Combined Anti-HIV-1 Activities of Emtricitabine and Tenofovir plus the Integrase Inhibitor Elvitegravir or Raltegravir Show High Levels of SynergyIn Vitro

2014 ◽  
Vol 58 (10) ◽  
pp. 6145-6150 ◽  
Author(s):  
Rima Kulkarni ◽  
Rebecca Hluhanich ◽  
Damian M. McColl ◽  
Michael D. Miller ◽  
Kirsten L. White
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Integrase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Strand Transfer ◽  
Antiretroviral Agents ◽  
Highly Active ◽  
Drug Classes ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTHighly active antiretroviral therapy (HAART) involves combination treatment with three or more antiretroviral agents. The antiviral effects of combinations of emtricitabine (FTC) plus tenofovir (TFV) plus antiretroviral agents of all the major drug classes were investigated. Combinations of FTC and TFV with a nonnucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz or rilpivirine) or with a protease inhibitor (PI) (atazanavir, lopinavir, or darunavir) showed additive to synergistic anti-HIV-1 activity. FTC-TFV with an HIV-1 integrase strand transfer inhibitor (INSTI) (elvitegravir or raltegravir) showed the strongest synergy. Anti-HIV-1 synergy suggests enhancement of individual anti-HIV-1 activities within cells that may contribute to potent treatment efficacy and open new areas of research into interactions between reverse transcriptase (RT) and integrase inhibitors.

scholarly journals Long-Term Effect of Different Classes of Highly Active Antiretroviral Therapy on Transaminases

2009 ◽  
Vol 1 (02) ◽  
pp. 077-081
Author(s):  
Ebele J Ikekpeazu ◽  
Emeka E Neboh ◽  
Ignatius C Maduka ◽  
Odutola Odetunde ◽  
Uche Ifejimalu
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Teaching Hospitals ◽  
Reverse Transcriptase Inhibitors ◽  
Hiv Patients ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Highly Active ◽  
Long Term Effect ◽  
Negative Controls

ABSTRACT AIM: The current use of highly active antiretroviral therapy (HAART) for HIV/AIDS patients has increased the recognition of their hepatotoxic effects. The present study is aimed at evaluating the level of aspartate transaminase (AST) and alanine transaminase (ALT) in HIV patients on different classes of HAART, for various durations, which causes its toxicity Materials and Methods: The AST and ALT levels were estimated in a total of 340 subjects, of which 290 were HIV positive subjects drawn from patients attending the HIV clinic in two Teaching Hospitals, in Nigeria. 240 of the HIV patients were divided into 3 equal groups of 80 each and placed on non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI), and protease inhibitors (PI), respectively, and were monitored for different periods of time (3, 6, 12, and >12 months). 50 of the HIV patients, yet to be placed on anti-retroviral therapy and 50 apparently healthy HIV-negative subjects served as the positive and negative controls, respectively. Results: A significant increase in enzyme levels was noted at three and six months in the NNRTI group, and at only three months in the NRTI and PI groups, when compared with the controls. However, increased ALT was observed at six months in those on PI. The increased ALT and AST levels noted in the NNRTI group were significant when compared to those on NRTI and PI over a three- and six-month duration. Conclusion: Liver enzyme activities were generally raised in the first three months of HAART, and further in the NNRTI group, after which they progressively fell to the normal level, with time. The highest degree was observed with NNRTIbased HAART.

Significant Toxicities Associated with Antiretroviral Therapy

2000 ◽  
Vol 13 (6) ◽  
pp. 457-474
Author(s):  
Tina J. Kanmaz ◽  
Nancy J. Lee
Keyword(s):  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Standard Of Care ◽  
Mitochondrial Toxicity ◽  
Reverse Transcriptase Inhibitors ◽  
Short Term ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Highly Active

Use of at least three potent antiretroviral agents has become the standard of care in the management of HIV infection. The potential toxicities associated with highly active antiretroviral therapy (HAART) however, may limit a patient’s ability to adhere to and tolerate these agents. Although a comprehensive discussion of all toxicities associated with HAART is beyond the scope of this article, selected short-term and long-term significant toxicities will be reviewed. Short-term toxicities that will be discussed include abacavir-induced hypersensitivity reactions, efavirenz-associated central nervous system side effects and rash associated with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitor (PI) amprenavir. Several long-term toxicities associated with the nucleoside reverse transcriptase inhibitors (NRTIs) are hypothesized to be due to mitochondrial toxicity. These toxicities include myositis and lactic acidosis with hepatic steatosis, pancreatitis and peripheral neuropathy. Some experts also hypothesize that mitochondrial toxicity is responsible for the lipodystrophy syndrome, which includes hyperglycemia, abnormal fat redistribution and dyslipidemia. Finally, indinavir-associated nephrolithiasis, which may present with either short term or long term use will be discussed. This article will provide the practicing pharmacist with a review of these significant toxicities, the implicated agents, incidence, usual clinical presentation, and recommendations for management.

An Overview of Antiretroviral Agents for Treating HIV Infection in Paediatric Population

2020 ◽  
Vol 27 (5) ◽  
pp. 760-794 ◽  
Author(s):  
Rita Melo ◽  
Agostinho Lemos ◽  
António J. Preto ◽  
Beatriz Bueschbell ◽  
Pedro Matos-Filipe ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Targeted Delivery ◽  
Highly Active Antiretroviral Therapy ◽  
Antiretroviral Drugs ◽  
Viral Reservoir ◽  
Reverse Transcriptase Inhibitors ◽  
Replication Process ◽  
Antiretroviral Agents ◽  
Multiple Drugs

Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To- Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process. These classes encompass Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs), Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs/NtRTIs), INtegrase Inhibitors (INIs), Protease Inhibitors (PIs), and Entry Inhibitors (EIs). Co-administration of certain antiretroviral drugs with Pharmacokinetic Enhancers (PEs) may boost the effectiveness of the primary therapeutic agent. The combination of multiple antiretroviral drug regimens (Highly Active AntiRetroviral Therapy - HAART) is currently the standard therapeutic approach for HIV infection. So far, the use of HAART offers the best opportunity for prolonged and maximal viral suppression, and preservation of the immune system upon HIV infection. Still, the frequent administration of high doses of multiple drugs, their inefficient ability to reach the viral reservoirs in adequate doses, the development of drug resistance, and the lack of patient compliance compromise the complete HIV elimination. The development of nanotechnology-based drug delivery systems may enable targeted delivery of antiretroviral agents to inaccessible viral reservoir sites at therapeutic concentrations. In addition, the application of Computer-Aided Drug Design (CADD) approaches has provided valuable tools for the development of anti-HIV drug candidates with favourable pharmacodynamics and pharmacokinetic properties.

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