MEDWATCH: Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) By  Stuart Katsh, MS, RD

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Pharmacologic Classification

• Seven antiretroviral agents are referred to as Nucleoside Reverse Transcriptase Inhibitors (NRTI’s). These medications are Zidovudine (Retrovir®) AZT or ZVD; Zalcitabine (Hivid®) ddC; Stavudine (Zerit®) d4T; Abacavir (Ziagen®) ABC; Lamivudine (Epivir®) 3TC; Emtricitabine (Emtriva®) FTC; and Didanosine (Videx® and Videx EC®) ddI. One NRTI is referred to  as a Nucleotide Reverse Transcriptase Inhibitor named Tenofovir (Viread®) TDF. All of these antiretroviral agents are approved by the Food and Drug Administration to treat HIV infection.

HIV Reverse Transcriptase

• The HIV Reverse Transcriptase enzyme is essential for HIV replication. The purpose of this enzyme is to allow synthesis of viral deoxyribonucleic acid (DNA) from ribonucleic (RNA). NRTIs are referred to as “Nucs”. They work by mimicking the nucleic acids that make up the HIV’s DNA strand. Once the NRTIs are incorporated into the growing HIV DNA strand, DNA synthesis is terminated, resulting in suppression of the HIV virus.

NRTIs, like all medications, have side effects. Reverse transcriptase closely resembles an enzyme found in mammalian mitochondria called DNA polymerase-gamma. The mitochondria produce energy for the cell through cellular aerobic respiration. Since NRTIs disrupt this process, some cells may die from the lack of energy resulting from mitochondrial toxicity. Other cells turn to an alternate source of energy, anaerobic metabolism. A byproduct of anaerobic metabolism for energy is lactic acid. Therefore lactic acidosis, which is characterized as the accumulation of lactic acid in the blood, is a potential side effect for all NRTIs. Symptoms are generally nonspecific but can include significant weakening of muscles in the legs and arms, abdominal pain, nausea, vomiting or breathing difficulty. Lactic acid levels can be measured in cases of suspected lactic acidosis, but routine screening is not recommended due to the naturally fluctuating nature of lactic acid.

Side effects such as nausea, vomiting, headache, diarrhea and anorexia are more commonly seen when two medications that have these similar side effects are taken as part of treatment therapy. 

• Another side effect attributed to NRTIs is lipodystrophy (first noted in the Nov/Dec 1998 HIV ReSource Review). Lipodystrophy is a redistribution of body fat/loss in some areas of the body and fat gain in other areas. Lipoatrophy is part of the definition of lipodystrophy and is an abnormal loss of subcutaneous fat, usually on the face, arms, legs or buttocks. Depletion of mitochondria (in part due to the NRTIs) can be the leading cause of lipoatrophy. While the NRTIs are most closely associated with lipoatrophy, there is data to show that they contribute to other types of lipodystrophy as well.