NRTIs inhibit HIV RNA-dependent DNA polymerase (reverse transcriptase) by acting as structural analogues for thymidine or adenosine when DNA is reverse transcribed inside cells leading to premature DNA chain termination and inhibition of viral replication. All NRTIs also have the potential to inhibit human intracellular DNA polymerases, including those necessary for mitochondria to replicate. Mitochondrial dysfunction is the source of many of the potential toxicities of this class of drug, particularly with older agents. Currently available nucleoside analogues are lamivudine (3TC), emtricitabine (FTC), abacavir (ABC) and zidovudine (AZT). Tenofovir is the only nucleotide analogue currently in use. Tenofovir DF and tenofovir TAF are orally bioavailable prodrugs of tenofovir, that are metabolised intracellularly into the active metabolite tenofovir diphosphate. Tenofovir DF is actively transported into proximal renal tubular cells, which is an important cause of its renal toxicity. Tenofovir AF is an alternative prodrug to tenofovir DF that is preferentially metabolised into the active metabolite in lymphocytes, allowing lower systemic doses to be administered that minimise renal toxicity without compromising virological efficacy. Both tenofovir AF and tenofovir DF achieve higher levels of drug absorption when co-administered with cobicistat or ritonavir. This results in the different recommended dosages for tenofovir AF. Emtricitabine, lamivudine, tenofovir DF and tenofovir AF also display activity against hepatitis B virus (HBV) and are recommended in HIV/HBV co-infected patients.
Importantly, many drugs in this class are available as fixed-dose combination (FDC) tablets. These tablets include earlier FDCs such as zidovudine/lamivudine (Combivir™) and zidovudine/lamivudine/abacavir (Trizivir™), and the currently recommended FDC tablets: tenofovir AF/emtricitabine (Descovy™), tenofovir DF/emtricitabine (Truvada™) and abacavir/lamivudine (Kivexa™). Moreover, tenofovir DF/emtricitabine has been coformulated with efavirenz (Atripla™), rilpivirine (Eviplera™) and with elvitegravir/cobicistat (Stribild™). More recently, tenofovir AF based combinations have become available: bictegravir /tenofovir AF/emtricitabine (Biktarvy™), elvitegravir/cobicistat/tenofovir AF/emtricitabine (Genvoya™), and tenofovir AF/emtricitabine/rilpivirine (Odefsey™) . Alternative FDC tablets to the tenofovir-based tablets are abacavir/lamivudine coformulated with dolutegravir (TriumeqTM) or dolutegravir/rilpivirine (Juluca™).
Importantly, the only NRTIs currently recommended for initial therapy in the US and European guidelines are the combinations of abacavir plus lamivudine and tenofovir (tenofovir DF or tenofovir AF) plus emtricitabine, plus a third agent. Abacavir should only be prescribed to people who test negative for HLA-B*5701, which accurately predicts the development of abacavir hypersensitivity syndrome and is carried by 5-8% of the Australian population[21]. Other NRTIs, including thymidine analogues, are no longer recommended, even as an alternative, largely because of unacceptable toxicity including, peripheral neuropathy, lipoatrophy, pancreatitis and lactic acidosis.
Guidelines for the dosing of NRTIs are shown in Table 1.
Table 1. Guidelines for NRTI dosing
|
Drug (dose per tablet) |
Dosing |
Food requirements |
Dose adjustment for renal impairment |
Dose adjustment for hepatic impairment |
|
Abacavir (300 mg) |
600 mg qd |
No |
No |
Yes, for people with mild hepatic impairment (Child-Pugh Class A), the dose recommended is 200mg BD (use Ziagen™ solution). Contraindicated if Child-Pugh Class B or C. |
|
Emtricitabine (200 mg) |
200 mg qd |
No |
Yes* |
No |
|
Lamivudine (300 mg or 150 mg) |
300 mg qd 150 mg bd |
No |
Yes* |
No |
|
Tenofovir (300 mg) |
300 mg qd |
No |
Yes* |
No |
|
Zidovudine (250 mg) |
250 mg bd |
No |
Yes, for very severe impairment * |
No, but AZT may accumulate due to a reduction in glucuronidation. Precise dosage recommendations are available, |
|
Co-formulated preparations |
||||
|
Kivexa™ (ABC 600 mg/ 3TC 300 mg) |
One tablet qd |
No |
Yes – do not use if CrCl |
|
|
Truvada™ (TDF 300 mg/ FTC 200 mg) |
One tablet qd |
No |
Yes. If CrCl is 30-49 L/min use |
No |
|
Descovy™ (TAF 10 mg/ FTC 200 mg) Descovy™ (TAF 25 mg/ FTC 200 mg) |
One tablet qd If prescribed with ritonavir or cobicistat boosted PI, use 10mg formulation |
No |
Yes. Do not use if CrCl < 30 mL/min |
No |
|
Combivir™ (AZT 300 mg / 3TC150 mg) |
One tablet bd |
No |
Yes. Do not use if CrCl < 50 mL/min |
No, but AZT may accumulate due to a reduction in glucuronidation. Precise dosage recommendations are available. |
|
Atripla™ (TDF 300 mg/ FTC 200 mg/ EFV 600 mg) |
One tablet qd nocte |
Take at night or before bedtime on an empty stomach to reduce side effects |
Yes. Do not use if CrCl < 50 mL/min |
Use with caution |
|
Eviplera™ (TDF 300 mg/ FTC 200 mg/ RPV 25 mg) |
One tablet qd |
Take with a meal. Contraindicated with proton pump inhibitors. Caution with any antacid use. |
Yes. Do not use if CrCl < 50 mL/min |
No |
|
Odefsey™ (TAF 25 mg/ FTC 200 mg/ RPV 25 mg) |
One tablet qd |
Take with a meal. Contraindicated with proton pump inhibitors. Caution with any antacid use. |
Yes. Do not use if CrCl < 30 mL/min |
No |
|
Stribild™ (TDF 300 mg/ FTC 200 mg/ EVG 150 mg/ cobicistat 150 mg) |
One tablet qd |
Take with food |
Yes. Do not use if CrCl < 70 mL/min. Discontinue if CrCl decreases below 50ml/min. |
Do not use in severe impairment |
|
Genvoya™ (TAF 10 mg/ FTC 200 mg/ EVG 150 mg/ cobicistat 150 mg) |
One tablet qd |
Take with food |
Yes. Do not use if CrCl < 30 mL/min |
Do not use in severe impairment |
|
Triumeq™ (Dolutegravir 50mg, ABC 600mg, lamivudine 300mg) |
One tablet qd |
No. |
Yes. Do not use if CrCl < 50 mL/min (use individual drugs) |
Yes, may need to use individual drugs in mild hepatic impairment (Child-Pugh Class A). Not recommended for people with mod-severe hepatic impairment (Child-Pugh Class B-C) |
|
Biktarvy™ (Bictegravir 50mg, TAF 25mg, FTC 200mg |
One tablet qd |
No |
Yes. Do not use if CrCl < 30 mL/min |
Child-Pugh Class A or B: No dose adjustment Child-Pugh Class C: Not recommended |
|
Juluca DTG 50mg, RPV 25mg |
One tablet qd |
Take with a meal Contraindicated with PPI therapy. Do not coadminister with calcium or magnesium supplements |
No dose adjustment necessary. In patients with CrCl <30 mL/min, monitor closely for adverse effects. |
Child-Pugh Class A or B: No dose adjustment Child-Pugh Class C: No dose recommendation
|
|
* check product information for change in dosing according to creatinine clearance |
||||
|
qd: once daily; bd: twice daily; nocte: at night; CrCl: creatinine clearance; EFV: efavirenz; RPV: rilpivirine; EVG: elvitegravir; TAF: tenofovir alafenamide fumarate |
||||