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.
[citation needed] RTIs come in four forms: The antiviral effect of NRTIs and NtRTIs is essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain.
However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs lack a 3′-hydroxyl group on the deoxyribose moiety.
As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5′–3′ phosphodiester bond needed to extend the DNA chain.
Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination.
[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.
NRTIs can induce mitochondrial impairment that leads to a number of adverse events, including symptomatic lactic acidosis.
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.
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.
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 .
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.