Term
| Maraviroc HIV Entry Inhibitor |
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Definition
There are 2 co-receptors that allow HIV entry into CD4 cells: CCR5 and CXCR4.
•Maraviroc is only effective at reducing viral load in patients with CCR5-tropic HIV strains; it is not effective against virus targeting the CXCR4 co-receptor or virus that use both receptors (i.e., dual-tropic HIV). |
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Term
| Maraviroc Pharmacokinetics |
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Definition
Maraviroc is administered orally.
–Maraviroc is a substrate for the efflux transporter P-glycoprotein (Pgp) and metabolized by the cytochrome P450 CYP3A.
–Its pharmacokinetics are affected by coadministration with inhibitors and inducers of these enzymes/transporters. |
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Term
| Maraviroc Adverse Effects. |
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Definition
| Because maraviroc antagonizes the CCR5 co-receptor located on some immune cells it could potentially increase the risk of developing infection. |
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Term
| Enfuvirtide T-20 HIV Fusion Inhibitor |
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Definition
| •Enfuvirtide binds gp41 preventing fusion and viral entry |
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Term
| Enfuvirtide T-20 HIV Fusion Inhibitor Description: |
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Definition
Enfuvirtide, also known as T-20,
–is a synthetic 36-amino-acid peptide derived from the HIV-1 envelope glycoprotein gp41
–interferes with the entry of HIV-1 into cells by inhibiting the fusion of viral and cellular membranes.
–should be reserved as a salvage therapy for individuals who have advanced disease |
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Term
| Enfuvirtide T-20 Pharmacokinetics |
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Definition
Enfuvirtide is administered as a subcutaneous (SC) injection.
–Enfuvirtide is a peptide and is expected to undergo catabolism to its constituent amino acids |
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Term
| Enfuvirtide T-20 Adverse Effects. |
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Definition
| An increased rate of bacterial respiratory infection (i.e., pneumonia |
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Term
| Enfuvirtide T-20 Drug Interactions. |
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Definition
| Ritonavir Increases the serum levels of Enfuvirtide. |
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Term
| Raltegravir Integrase Inhibitors |
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Definition
Raltegravir is an HIV integrase strand transfer inhibitors
•Integrase catalyzes the integration of the viral DNA in the cellular (target) DNA by strand transfer.
•Inhibition of integrase by raltegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus.
•Used only in combination with other antiretroviral agents. |
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Term
| Nucleoside and Nucleotide RT Inhibitors |
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Definition
Nucleoside analog inhibitors need to be metabolically activated within cells by phosphorylation.
1.The resulting 5-′triphosphates can inhibit the RT enzyme by substrate competition and chain termination
2.The lack of a 3'-OH group in the incorporated nucleoside analog prevents the formation of 5' to 3' phosphodiester linkage essential for DNA chain elongation
3.viral DNA growth is terminated and production of new virions is inhibited.
2.Nucleotide reverse transcriptase inhibitors (NtRTIs) have a similar mode of action to NRTIs, but only two phosphorylation steps by cellular kinases are required for conversion to the active metabolite.
1.NtRTIs are therefore able to bypass the nucleoside-kinase reaction
2.More stable phosphonate bonds can no longer be cleaved by the esterases |
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Term
| Nucleoside RT Inhibitors NRTI |
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Definition
NRTIs can be differentiated upon their activity in proliferating or non-proliferating cells
–Some NRTIs may be preferentially activated in proliferating cells or may be cell-activation independent and have increased activity in resting cells.
–Zidovudine and stavudine are more active in dividing cells,
–didanosine, zalcitabine and lamivudine are more active in resting cells
•Adverse Reactions:
– as a class all NRTI cause lactic acidosis > This can lead to hepatomegaly with steatosis
–Mitochondrial dysfunction |
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Term
| Zidovudine ZDV or AZT Nucleoside Reverse Transcriptase Inhibitor NRTI |
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Definition
Zidovudine (formerly called azidothymidine [AZT]) is a nucleoside reverse transcriptase inhibitor (NRTI).
–Was first investigated as an antineoplastic drug.
–Due to the development of resistance, zidovudine is not recommended to be given as monotherapy
–Activity is dependent upon intracellular conversion to zidovudine 5'-triphosphate (ZDV-TP) |
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Term
| Nucleoside RT Inhibitors NRTI Adverse Effects |
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Definition
Major adverse effect of zidovudineis bone marrow toxicity resulting in severe anemia and/or neutropenia.
–Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases |
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Term
| Lamivudine 3TC Nucleoside Reverse Transcriptase Inhibitor NRTI |
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Definition
Lamivudine (3TC) is an NRTI used as an antiviral agent in the treatment of HIV and HBV infections.
•Initially effective as monotherapy, resistance develops within 12 weeks; therefore the optimal use of lamivudine is as part of a 3-drug regimen.
•Lamivudine is a potent reverse-transcriptase inhibitor. It has been shown to inhibit both type 1 and type 2 HIV reverse transcriptase.
•Lamivudine can also inhibit replication of hepatitis B virus (HBV) and cellular DNA polymerase |
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Term
| Nucleotide RT Inhibitors NtRTI |
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Definition
Nucleotide reverse transcriptase inhibitors (NtRTIs) have a similar mode of action to NRTIs, but only two phosphorylation steps by cellular kinases are required for conversion to the active metabolite.
•NtRTIs are therefore able to bypass the nucleoside-kinase reaction
•More stable phosphonate can no longer be cleaved by esterases |
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Term
| Nucleotide RT Inhibitors NtRTI mechanism |
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Definition
The mechanism of action of tenofovir (PMPA) is similar to that of adefovir (PMEA shown here). As acyclic nucleoside phosphonates, adefovir and tenofovir only need two phosphorylations (instead of three, as is the case for acyclic nucleoside analogues such as acyclovir and ganciclovir discussed in Herpes virus section) to be converted to their active (diphosphorylated) forms. The diphosphorylated forms then act as chain terminators of the DNA synthesis catalysed by their target enzyme, Reverse transcriptase for human immunodeficiency virus or hepatitis B virus.
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Term
| Tenofovir PMPA Nucleotide Reverse Transcriptase Inhibitor NtRTI |
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Definition
Tenofovir (also known as PMPA) is acyclic nucleoside phosphonate (nucleotide) diester analog of adenosine monophosphate and is available as an ester prodrug, tenofovir disoproxil fumarate (tenofovir DF)-Viread.
–Tenofovir exhibits activity against HIV-1 viruses with reduced sensitivity to nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).
–Tenofovir inhibits viral reverse transcriptase and acts as a DNA chain terminator.
–Tenofovir also inhibits hepatitis B virus (HBV) infection. |
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Term
| Tenofovir PMPA Nucleotide Reverse Transcriptase Inhibitor NtRTI Pharmakokinetics |
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Definition
Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir.
–Tenofovir is then taken up by cells and undergoes phosphorylation to form tenofovir diphosphate (PMPApp).
–Tenofovir's activity is additive or synergistic when combined with other antiretroviral agents.
Prof. Stella |
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Term
| Nonnucleoside RT Inhibitors (NNRTI) |
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Definition
•NNRTI developed by screening large libraries of compounds for the ability to inhibit recombinant HIV RT
•all are noncompetitive inhibitors of the enzyme
•specific for HIV-1 RT. HIV-2 RT is not inhibited by NNRTIs
•NNRTI do not compete with template or dNTPs and do not require phosphorylation for activity
•NNRTIs interact with an allosteric binding site on HIV-1 RT distinct from where NRTIs bind
•Resistance to NNRTI develops rapidly |
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Term
| Nevirapine , delavirdine and efavirenz Non-nucleoside reverse transcriptase inhibitors NNRTI |
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Definition
Mechanism of Action:
–As opposed to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) do not require intracellular activation and are not active against HIV-2.
–NNRTIs bind directly and noncompetitively to the RT enzyme at a site distinct from the NRTI binding site. All of these agents bind to the same site,
–NNRTIs block DNA polymerase by causing a conformational change and disrupting the catalytic site of the enzyme |
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Term
| Nevirapine , delavirdine and efavirenz Non-nucleoside reverse transcriptase inhibitors NNRTI Adverse Reactions: |
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Definition
Rash is a common. Individually: nevirapine associated with hepatotoxicity, and nevirapine with CNS symptoms
–Resistance develops rapidly to NNRTIs when given as monotherapy and resistance to one agent usually infers cross-resistance to the rest of the class. |
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Term
| HIV Protease (PR) Inhibitors |
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Definition
Viral protease cleaves the Gag and Gag-Pol polyproteins. These cleavages produce the mature viral core proteins and virus-specific, core-associated enzymes
•The development of HIV-1 PR inhibitors relied heavily on previous work with aspartyl PRs such as renin and on a precise knowledge of the crystallographic structure of the HIV PR enzyme
•“Rational drug design” based on the crystal structure of protease and of the structure-activity relationships led to the development of nonpeptidyl PR inhibitors. |
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Term
| HIV PR inhibitors Mechanism of Action |
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Definition
•HIV-1 protease cleaves a Phe-Pro peptide bond of the HIV polyprotein
•Analogs of HIV-1 polypeptide replace the cleavable bond of the viral polyprotein, Phe–Pro, with transition state mimics and a non-hydrolyzable hydroxyethylene, hydroxyethylamine, or phosphinate groupa. The protease inhibitors mimic the structure of the viral PR’s regular substrate, and compete with its binding, thus blocking protease activity. Except for tipranavir, all other HIV protease inhibitors can be considered as peptidomimetic in that they contain the non-scissile (non-cleavable) hydroxyethylene [-CH2-CHOH-] bond instead of the readily hydrolysable peptide [-CO-NH-] bond. b HIV protease structure with darunavir (TMC114) in the active site |
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Term
| Ritonavir Anti-Retroviral Protease Inhibitors |
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Definition
Ritonavir is a competitive inhibitor of HIV protease responsible for cleaving gag-pol precursor molecules to produce the final structural proteins of a mature virion core
–Protease inhibition renders the virus noninfectious.
–Ritonavir inhibits both HIV-1 and HIV-2 proteases. |
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Term
| Ritonavir Anti-Retroviral Protease Inhibitors Drug Interactions. |
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Definition
Ritonavir is a substrate and a potent inhibitor CYP3A4.
–In concurrent use with other therapies many clinically significant drug interactions are possible.
–Ritonavir can act as a pharmacokinetic enhancer of drugs metabolized by the cytochrome P450 3A metabolic enzymes which are expected to have large (> 3x) increases in bioavailability when coadministered with ritonavir. |
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Term
| Ritonavir Adverse Effects. |
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Definition
| Hyperlipidemia, with large increases in total cholesterol and triglyceride concentrations ->Lipodystrophy syndrome including central obesity |
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Term
| Tipranavir Anti-Retroviral Protease Inhibitors |
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Definition
Tipranavir is a non-peptidic protease inhibitor
•Tipranavir was developed from a nonpeptidic coumarin template and its antiprotease activity was discovered by high-throughput screening
•HIV strains in patients who have previously received and developed resistance to other PIs are responsive to tipranavir.
•Adverse Effects. Dose-dependent hepatotoxicity, lipodystrophy |
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Term
| Human Immunodeficiency Virus (HIV) |
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Definition
Problems with Therapy
–Mutation rate of RT is 1/104
–Genome is 104 bases
•1010 unique virions are produced every day in an HIV-infected individual,
•not all new variants are more infectious or more resistant to therapy or immune recongnition
•Selection by active therapy or immune system leads to evolution of viral strains that adapt to host immune response and to antiviral therapy
•In addition many subtypes already present worldwide
–Recombination between HIV variants can also contribute significantly to genetic variation in vivo
means 1 base mismatch for every new virion |
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Term
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Definition
Highly Active Antiretroviral Therapy
No anti-HIV drug shows long-term suppressive benefit when used individually
•Combination Works:
•Additive or synergistic in vitro antiviral activity is usually seen when a nucleoside analog is used together with a nonnucleoside RT inhibitor.
•Careful when using same class of inhibitors due to class-wide resistance
•Triple therapy can use an NRTI+NNRTI+PR inhibitor combination to reduce viral RNA to less than 50 copies/ml.
•Probability of resistance emerging at such low level of replication is reduced. But complicated administration schedules and adverse effects of combination therapy can reduce compliance. |
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Term
HAART
Contraindications and Precautions |
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Definition
•Interruption.
•Unplanned antiretroviral therapy interruption may sometimes be necessary
•Antiretroviral regimen contains drugs with differing half-lives
•Stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life, this can lead to development of resistant strains for the more long-lived drug
HAART
Contraindications and Precautions |
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Term
| Human Immunodeficiency Virus (HIV) |
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Definition
Problems with HAART
–AIDS related lipodystrophy and insulin resistance.
–VPr protein also acts as an activator of glucocorticoid receptor and suppresses insulin production.
–HIV lipodystrophy syndrome in patients receiving long-term highly active antiretroviral therapy (HAART) |
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Term
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Definition
| Antiretroviral drugs can prevent sexual transmission of HIV among couples in which one partner has HIV and the other does not |
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