What are the adverse effects of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Adverse effects of the NRTI class include mitochondrial toxicities (e.g., lactic acidosis, pancreatitis, peripheral neuropathy, hepatic steatosis, lipoatrophy). [8] Mitochondrial toxicities are due to NRTI binding to human mitochondrial DNA polymerase-γ enzyme, impairing cellular respiration. Under these conditions, normal aerobic metabolism shifts to an anaerobic process, resulting in the above manifestations.

Antiretroviral therapy reduces the risk of chronic kidney disease along with CD4 cell restoration and suppression of plasma viral load, despite an increased risk that is associated with initial treatment regimens that include tenofovir DF plus a ritonavir-boosted protease inhibitor. [18]

Binding affinity for mitochondrial DNA polymerase-γ by each NRTI is predictive of adverse-effect potential and varies as follows (in decreasing order of affinity): zalcitabine, didanosine, stavudine, lamivudine/emtricitabine, zidovudine, abacavir, and tenofovir. [19, 20]

Individual drug-specific adverse effects include bone marrow suppression, myopathy, and headache with zidovudine and a systemic hypersensitivity reaction with abacavir. [8] Abacavir and didanosine have been associated with an increased risk for adverse cardiovascular events. [21]

Initiation of ART is associated with increased bone turnover and bone loss from the spine and hip, with a number of subjects losing about 6% bone mass density within 1 year after starting treatment. [22] Adverse effects with the remaining NRTIs are outlined in greater detail in U.S. ART treatment guidelines. [8]

Although not recommended for patients with severe renal impairment, those with moderate renal impairment can take tenofovir AF. Tenofovir AF appears to be associated with less kidney toxicity and less decreases in bone density than previously approved tenofovir-containing regimens. [14, 23] Patients given elvitegravir/cobicistat/emtricitabine/tenofovir AF had significantly smaller mean serum creatinine increases than those given elvitegravir/cobicistat/emtricitabine/tenofovir DF (0.08 vs 0.12 mg/dL; P< 0.0001), significantly less proteinuria (median % change -3 vs 20; P< 0.0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; P< 0·0001) and hip (-.0·66 vs -2·95; P< 0.0001) at 48 weeks. [14]

In clinical trials, patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) showed greater increases in serum lipids (total cholesterol and low-density lipoprotein) than those receiving other ART regimens, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. [14]

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