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Nucleoside Reverse Transcriptase Inhibitor


Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.




nucleoside reverse transcriptase inhibitor



When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation, to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.[citation needed]


In contrast, NNRTIs have a completely different mode of action. NNRTIs block reverse transcriptase by binding directly to the enzyme. NNRTIs are not incorporated into the viral DNA like NRTIs, but instead inhibit the movement of protein domains of reverse transcriptase that are needed to carry out the process of DNA synthesis. NNRTIs are therefore classified as non-competitive inhibitors of reverse transcriptase.[citation needed]


Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs) compose the first class of antiretroviral drugs developed. In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates. This phosphorylation step is carried out by cellular kinase enzymes. NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis.[2]


As described above, host cells phosphorylate nucleoside analogs to nucleotide analogs. The latter serve as poison building blocks (chain terminators) for both viral and host DNA, causing respectively the desired antiviral effect and drug toxicity/side effects. Taking phosphonate nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs) directly obviates the initial phosphorylation step, but host enzymes must still phosphorylate the phosphonate nucleotide analogue to the phosphonate-diphosphate state for anti-viral activity. These molecules were first synthesized by Antonin Holy at the Czech Academy of Sciences, and commercialized by Gilead.[citation needed]


Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) are the third class of antiretroviral drugs that were developed. In all cases, patents remain in force until beyond 2007. This class of drugs was first described at the Rega Institute for Medical Research (Belgium).[citation needed]


While NRTIs and NNRTIs alike are effective at terminating DNA synthesis and HIV replication, HIV can and eventually does develop mechanisms that confer the virus resistance to the drugs. HIV-1 RT does not have proof-reading activity. This, combined with selective pressure from the drug, leads to mutations in reverse transcriptase that make the virus less susceptible to NRTIs and NNRTIs.Aspartate residues 110, 185, and 186 in the reverse transcriptase polymerase domain are important in the binding and incorporation of nucleotides. The side chains of residues K65, R72, and Q151 interact with the next incoming nucleotide. Also important is L74, which interacts with the template strand to position it for base pairing with the nucleotide. Mutation of these key amino acids results in reduced incorporation of the analogs.


There are two major mechanisms of NRTI resistance. The first being reduced incorporation of the nucleotide analog into DNA over the normal nucleotide. This results from mutations in the N-terminal polymerase domain of the reverse transcriptase that reduce the enzyme's affinity or ability to bind to the drug . A prime example for this mechanism is the M184V mutation that confers resistance to lamivudine (3TC) and emtricitabine (FTC).[4][5] Another well characterized set of mutations is the Q151M complex found in multi-drug resistant HIV which decreases reverse transcriptase's efficiency at incorporating NRTIs, but does not affect natural nucleotide incorporation. The complex includes Q151M mutation along with A62V, V75I, F77L, and F116Y.[6][7] A virus with Q151M alone is intermediately resistant to zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and slightly resistant to abacavir (ABC).[8][9] A virus with Q151M complexed with the other four mutations becomes highly resistant to the above drugs, and is additionally resistant to lamivudine (3TC) and emtricitabine (FTC).[9][10]


NNRTIs do not bind to the active site of the polymerase but in a less conserved pocket near the active site in the p66 subdomain. Their binding results in a conformational change in the reverse transcriptase that distorts the positioning of the residues that bind DNA, inhibiting polymerization.[14] Mutations in response to NNRTIs decrease the binding of the drug to this pocket. Treatment with a regimen including efavirenz (EFV) and nevirapine (NVP) typically results in mutations L100I, Y181C/I, K103N, V106A/M, V108I, Y188C/H/L and G190A/S.[15]There are three main mechanisms of NNRTI resistance. In the first NRTI mutations disrupt specific contacts between the inhibitor and the NNRTI binding pocket. An example of this is K103N and K101E which sit at the entrance of the pocket,[16][17] blocking the entrance/binding of the drug. A second mechanism is the disruption of important interactions on the inside of the pocket. For example, Y181C and Y188L result in the loss of important aromatic rings involved in NNRTI binding.[18][19] The third type of mutations result in changes in the overall conformation or the size of the NNRTI binding pocket. An example is G190E, which creates a steric bulk in the pocket, leaving little or no room for an NNRTI to tightly bind.[20][21]


Reverse transcriptase inhibitors are medications used in the management and treatment of HIV. It is in the antiretroviral class of drugs. This activity reviews the indication, action, and contraindications for RTIs as a valuable agent in managing HIV (and other disorders when applicable). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional healthcare team in the (management of patients with HIV and related conditions.


Objectives:Identify the mechanism of action of reverse transcriptase inhibitors.Describe the potential adverse effects when patients receive reverse transcriptase inhibitors.Review appropriate monitoring during therapy with reverse transcriptase inhibitors.Summarize interprofessional team strategies for improving care coordination and communication to advance reverse transcriptase inhibitor use and improve outcomes.Access free multiple choice questions on this topic.


With the rise of the HIV/AIDS epidemic, numerous companies have created medications to hopefully decrease the spread and potentially cure this problem. At the forefront of these medications are the reverse transcriptase inhibitors. To date, the FDA has approved the use of reverse transcriptase inhibitors for two main viral infections. The first approved use is for the treatment of HIV, specifically the HIV-1 strain. The second virus is hepatitis B.[1] Reverse transcriptase inhibitors have also been used for post-exposure prophylaxis when concern exists for potential patient infection with HIV. Lastly, reverse transcriptase inhibitors are being used to decrease the spread of HIV from mother to child during pregnancy and labor and delivery.[2] The drug of choice for HIV treatment of the mother during pregnancy is zidovudine-based antiretroviral therapy.


Research and trials are currently underway to assess the efficacy of reverse transcriptase inhibitors for pre-exposure prophylaxis. Studies show that there is anywhere from a 67% to 75% reduction in the risk of becoming infected by using pre-exposure prophylaxis.[3] While the results have been promising, some have raised strong concerns for the emergence of drug-resistant strains due to a lack of adherence to pre-exposure prophylaxis protocol by patients. The most significant factor in the success of these therapies has been the lack of adherence to the protocol by patients.[2]


Within the class of reverse transcriptase inhibitors are two subclasses of drugs. The first class is the nucleoside/nucleotide reverse transcriptase inhibitors, and the second class is the non-nucleoside reverse transcriptase inhibitors.


Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the second class of reverse transcriptase inhibitors. The primary mechanism of action is through the binding of the NNRTI to the reverse transcriptase and the creation of a hydrophobic pocket proximal to the active site. This pocket creates a new spatial configuration of the substrate-binding site to reduce the overall polymerase activity. By creating a different configuration, DNA synthesis becomes slowed overall. Because of the non-competitive inhibitor action of NNRTI, it is not effective against HIV-2 reverse transcriptase.[4]


The following list contains some of the approved drugs that fall in the NRTI and NNRTI categories of reverse transcriptase inhibitors and the dose ranges for each drug. All RTIs come in an oral tablet or solution form, with certain drugs coming in other formulations.


While reverse transcriptase inhibitors are generally safe to use, contraindications do exist to prevent severe adverse effects associated with their use. First and foremost, a prior history of hypersensitivity to RTIs is a contraindication for their use. If a patient has had an adverse reaction to one RTI, they should discontinue the drug and a different agent prescribed.


Toxicity to RTIs mainly occurs via adverse reactions that the patient may present with (see above for a list of severe reactions). Patients should understand the serious adverse effects the drugs that make up their HAART regimen can cause. If a patient presents with an adverse effect, then the drug should be discontinued and replaced with another from the same subclass of reverse transcriptase inhibitors. Specifically for stavudine, studies suggest that switching to abacavir will help improve lipodystrophy and still maintain optimal regimen efficacy.[16] All other drugs causing adverse reactions require switching to a drug to which their specific HIV genotype is susceptible. 041b061a72


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