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How do nucleotide reverse transcriptase inhibitors differ from nucleoside reverse transcriptase inhibitors?

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Diagram illustrating the process of retrovirus infection and reverse transcription, showing a retrovirus entering a host cell, releasing viral RNA, reverse transcriptase converting RNA to DNA, integration into the host genome, transcription of new viral RNA, assembly of new virions, and budding from the cell. — Reverse transcriptase After a retrovirus infects a cell, an enzyme known as reverse transcriptase converts viral RNA into proviral DNA in the cytoplasm. Proviral DNA then enters the nucleus, where it is incorporated into the host cell's DNA.

Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) are both classes of drugs used to block the reverse transcriptase enzyme, which HIV uses to convert viral RNA into DNA.12

The primary difference between these two groups lies in their activation process within the body:

Nucleoside RT inhibitors (NRTIs): These drugs are not active in their administered form. To become effective, they must undergo phosphorylation—a process of cellular processing—to be converted into their active state.1
Nucleotide RT inhibitors (NtRTIs): These drugs are considered "preactivated." Because they are already phosphorylated, they require less cellular processing to begin inhibiting the viral enzyme.1

Despite this difference in activation, both classes function similarly once active: they mimic natural nucleosides or nucleotides and are incorporated by reverse transcriptase into the growing viral DNA strand. This incorporation terminates DNA synthesis, thereby preventing the virus from replicating. NtRTIs were specifically developed to help combat the emergence of drug-resistant HIV strains.12