Reverse transcriptase inhibitors
Reverse transcriptase inhibitors (RTIs) are antiviral medications primarily used to treat human immunodeficiency virus (HIV) infections. They function by interfering with the reverse transcriptase enzyme, which HIV uses to convert its RNA genetic material into DNA, enabling its replication within human T cells. There are two main classes of RTIs: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), which compete with natural deoxynucleotides to integrate into the viral DNA, and non-nucleoside reverse transcriptase inhibitors (NNRTIs), which block the enzyme without being incorporated into the DNA. Notable examples of RTIs include zidovudine (AZT), emtricitabine, and nevirapine.
The development of these medications has significantly transformed the management of HIV, shifting the perception of AIDS from a terminal illness to a chronic, manageable condition. However, due to rapid drug resistance, RTIs are typically used as part of combination therapies known as highly active antiretroviral therapy (HAART), which involves at least three different medications from various classes. This approach enhances the effectiveness of treatment and helps to prevent the virus from developing resistance. Overall, RTIs remain a critical component of HIV treatment regimens, highlighting their importance in addressing this global health challenge.
Reverse transcriptase inhibitors
- ALSO KNOWN AS: Non-nucleoside reverse transcriptase inhibitors (non-nukes), nucleoside analogues, nucleoside and nucleotide reverse transcriptase inhibitors (nukes)
Definition
Reverse transcriptase inhibitors (RTIs) are antiviral drugs that treat human immunodeficiency virus (HIV) infection. Two types of RTIs are discussed here.
Mechanism of Action
RTIs incorporate into the deoxyribonucleic acid (DNA) of HIV and stop it from reproducing. More specifically, HIV contains genetic information in the form of ribonucleic acid (RNA); when HIV infects a human T cell (or lymphocyte), it assembles a new HIV DNA chain by combining its own RNA with some of the DNA of the infected human cell. To do this, it uses an enzyme called reverse transcriptase. RTIs prevent the reverse transcriptase enzyme from working. Therefore, incomplete DNA is synthesized and, thus, cannot be used to create a new copy of the virus.
NRTIs and NNRTIs
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of drugs that thwart the function of the reverse transcriptase enzyme in two different ways. NRTIs (or nukes) compete with deoxynucleotides from the human T cell for incorporation into the DNA that the HIV is assembling. NRTIs are analogues of these naturally occurring deoxynucleotides and are classified as competitive substrate inhibitors. In contrast, NNRTIs (or non-nukes) are not incorporated into the new viral DNA chain but physically block the protein domains of reverse transcriptase that are needed for DNA synthesis. NNRTIs are classified as noncompetitive inhibitors of reverse transcriptase.
The following drugs were available RTIs in 2025: zidovudine (Retrovir), lamivudine (Epivir), abacavir sulfate (Ziagen), emtricitabine (Emtriva), tenofovir disoproxil fumarate (Viread), lamivudine and zidovudine (Combivir), abacavir and lamivudine (Epzicom), abacavir, zidovudine, and lamivudine (Trizivir), tenofovir disoproxil fumarate and emtricitabine (Truvada), tenofovir alafenamide and emtricitabine (Descovy).
In 1981, the Centers for Disease Control and Prevention (CDC) reported five cases of pneumonia of unknown cause in Los Angeles County, sparking widespread medical and media attention and marking awareness of a new disease that would become known as AIDS (acquired immunodeficiency syndrome). By the beginning of 1987, the World Health Organization had been notified of 43,880 cases of AIDS worldwide. AIDS, and the fear and prejudice against people with HIV infection, had spread widely and rapidly. The same year, the U.S. Food and Drug Administration (FDA) approved the first drug indicated for the treatment of HIV infection: the NRTI known as zidovudine, or azidothymidine (AZT). Zidovudine had an enormous effect on the disease; it also had an effect on the way AIDS as a disease was perceived. People began to think of AIDS as a chronic, but manageable disease, and not as a death sentence.
Soon came the need for drugs with better resistance; zidovudine slows HIV significantly, but it does not stop it entirely. NNRTIs became the third class of HIV drugs indicated for the treatment of HIV infection (after protease inhibitors). The first NNRTI, nevirapine, was approved by the FDA in 1996. There are now six different classes of HIV drugs that act on different targets. The most popular target remains the reverse transcriptase enzyme, and both nukes and non-nukes remain central to HIV drug therapy.
Drug resistance develops quickly with monotherapy, and NRTIs and NNRTIs are always used in conjunction with other drugs, either as an ingredient (as in Combivir and Trizivir) or as part of combination therapy. This combination therapy is called highly active antiretroviral therapy (HAART), for which a minimum of three drugs from different classes are combined.
Bibliography
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De Béthune, Marie-Pierre. “Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Their Discovery, Development, and Use in the Treatment of HIV-1 Infection.” Antiviral Research 85, no. 1 (2010): 75-90.
De Clercq, Erik. “Antiviral Drug Discovery and Development: Where Chemistry Meets with Biomedicine.” Antiviral Research 67, no. 2 (2005): 56-75.
Skowron, Gail, and Richard Ogden, eds. Reverse Transcriptase Inhibitors in HIV/AIDS Therapy. New York: Humana Press, 2006.
"What to Know About Treating HIV With NRTIs." Medical News Today, 29 June 2022, www.medicalnewstoday.com/articles/nrtis. Accessed 4 Feb. 2025.