Nucleoside reverse transcriptase inhibitors (NRTIs) are antiviral drugs that were the first class of medication developed to combat the human immunodeficiency virus (HIV). As a core component of many treatment regimens, they slow the progression of viral illnesses. NRTIs interfere with a virus’s ability to replicate, helping to control the infection. Their introduction significantly changed the course of treatment for diseases like HIV.
The Mechanism of NRTIs
NRTIs disrupt a process called reverse transcription. Viruses like HIV are retroviruses, meaning their genetic material is RNA. To replicate inside a host cell, these viruses must convert their RNA into DNA using an enzyme called reverse transcriptase. This new viral DNA is then integrated into the host cell’s genetic material, turning the cell into a factory for producing more viruses.
NRTIs are synthetic compounds that mimic the natural nucleosides used to build DNA. However, these “impostor” nucleosides are faulty, missing a chemical group required to form the next link in the DNA chain. Before they can work, NRTI drugs must be activated within the host cell through phosphorylation, where cellular enzymes add phosphate groups to them.
Once activated, these faulty building blocks are incorporated by the viral reverse transcriptase into the new strand of viral DNA. Because the NRTI lacks the correct structure, no further nucleosides can be added after it. This action halts the DNA-building process in an event known as chain termination, preventing the virus from successfully replicating.
Therapeutic Uses of NRTIs
NRTIs are a component of combination antiretroviral therapy (ART), the standard treatment for HIV. In ART, NRTIs are used with drugs from other classes that target different stages of the HIV lifecycle. This multi-pronged attack is effective at suppressing the virus, often reducing it to undetectable levels in the blood. This allows the immune system to recover and prevents the progression to acquired immunodeficiency syndrome (AIDS).
NRTIs are also used for HIV prevention. Pre-Exposure Prophylaxis (PrEP) involves individuals at high risk for HIV taking a daily NRTI-containing pill to prevent infection. Post-Exposure Prophylaxis (PEP) is a short-term course of NRTIs and other antiretrovirals taken after a potential exposure to stop the virus from establishing itself.
NRTIs also treat chronic hepatitis B virus (HBV) infection, as HBV uses a similar reverse transcriptase enzyme to replicate. Certain NRTIs, like tenofovir and lamivudine, inhibit this enzyme and are approved for long-term management of chronic hepatitis B. They help reduce HBV levels, decrease liver inflammation, and slow the progression to serious liver damage like cirrhosis and liver cancer.
Examples of NRTI Drugs
The NRTI class includes medications developed over several decades. Zidovudine (AZT) was the first antiretroviral approved for HIV, but newer agents have improved efficacy and safety profiles. Common NRTIs include Lamivudine (3TC), Abacavir (ABC), and Emtricitabine (FTC). Two widely used NRTIs are different formulations of tenofovir: Tenofovir Disoproxil Fumarate (TDF) and the newer Tenofovir Alafenamide (TAF).
TAF was designed to deliver the active drug more efficiently to target cells. This results in lower drug levels in the bloodstream and a reduced risk of certain side effects compared to the older TDF. To improve patient convenience, companies often combine two or more drugs into a single pill. Many of these co-formulations include two NRTIs, such as Truvada (TDF/Emtricitabine), Descovy (TAF/Emtricitabine), and Biktarvy.
Associated Side Effects
NRTIs can cause a range of side effects. Milder effects include nausea, headache, and a general feeling of malaise, which may subside as the body adjusts. A more serious concern, particularly with older NRTIs, is mitochondrial toxicity. This occurs when the drugs interfere with the replication of human mitochondrial DNA.
Mitochondrial toxicity can lead to several complications. A buildup of lactic acid (lactic acidosis) is a rare but potentially life-threatening condition linked to older drugs. Other toxicities include inflammation of the pancreas (pancreatitis) and an abnormal redistribution of body fat (lipodystrophy). Newer NRTIs have a much lower risk of causing mitochondrial toxicity.
Modern NRTIs are considered safer but still carry potential side effects. For instance, tenofovir has been linked to effects on kidney function and bone mineral density. The older TDF formulation carries a higher risk for these issues than the newer TAF. Regular monitoring by a healthcare provider is standard for people taking NRTIs to manage any adverse effects.