Nucleoside RT inhibitors

The first approved antiretroviral drugs were nucleoside reverse transcriptase inhibitors (NRTIs), also known as nucleoside analogues. Before they can be used within a cell, NRTIs must be converted from their original forms into their active triphosphate forms by a three-step process known as phosphorylation. These NRTI triphosphates resemble the nucleotide building blocks that naturally occur in human cells .

The licensed NRTIs, listed by abbreviation, generic, and trade name, are:

• 3TC    lamivudine (Epivir)
• ABC   abacavir (Ziagen)
• AZT   zidovudine (Retrovir)
• d4T    stavudine (Zerit)
• ddC   zalcitabine (Hivid. Note: withdrawn from the market in 2005)
• ddI    didanosine (Videx/VidexEC, enteric-coated)
• FTC   emtricitabine (Emtriva).

Further drug development in this class has almost come to a halt.

Apricitabine (ATC, AVX754, and formerly SPD-754) was in phase III development and had been ‘fast tracked’ by the US Food and Drug Administration (FDA). The drug’s developer, Avexa, released 96-week data from its ongoing phase II study that show no reports of serious adverse events or of resistance. The drug, a deoxycytidine analogue, is active against the M184V mutation as well as other thymidine-associated mutations. Apricitabine seems to avoid the mitochondrial toxicity found in first-generation NRTIs and has been safely and effectively used in treatment-naive and ART-experienced individuals and no resistance to the drug has been seen. Viral load is undetectable in 85% of the 39 individuals who completed 96 weeks on therapy. However, despite promising results Avexa, who took over development from Shire Pharmaceutical, announced in 2010 that it would not move ahead with the development of the drug because it did not have a sufficiently distinct market niche. The future of the drug is now unclear.^{1 2 3}

Elvucitabine (ELV and formerly ACH-126) is a cytosine analogue similar to 3TC and FTC that is also active against hepatitis B . It is being developed by Achillion Pharmaceuticals in partnership with a Chinese manufacturer for treatment of people coinfected with HIV and hepatitis B. Interim 48-week data from a phase II trial in treatment-naive patients shows elvucitabine and 3TC having comparable viral suppression and CD4 cell responses with a similar safety profile and little difference in side-effects. Because of its 90-hour half-life, elvucitabine is a good prospect for co-formulation with other antiretrovirals for once-daily dosing. A similar phase II trial in treatment-experienced patients is underway.⁴

Racivir (RCV), by Pharmasset Inc, is an oxothiolane NRTI similar to FTC and 3TC. In animal studies, it was active against HIV-1 and hepatitis B. Racivir was effective in reducing viral load in patients who had the M184V and less than three thymidine analogue mutations. It was thought that the drug might be positioned as second-line therapy in patients resistant to 3TC. It was effective in phase I and II clinical trials amongst treatment-experienced patients when given with d4T and efavirenz (Sustiva). Plans for phase II/III clinical trials have not yet moved forward, and Pharmasset is now looking for a development partner to take the drug further.

For further information on specific NRTIs, see A to Z of antiretroviral drugs.