Antiretroviral drugs are used to treat HIV infection. They work by blocking a stage of the virus’s life cycle and, by doing so, prevent the virus from replicating. The drugs are organized into six different classes based largely on the stage of the life cycle they inhibit.

As of 2021, the Food and Drug Administration has granted approval to 26 individual drug agents and 22 fixed-dosed combination (FDC) drugs comprised of two or more antiretrovirals. This includes the first antiretroviral drug regimen, called Cabenuva, which requires a once-a-month or once-every-two-months injection rather than having to take an oral dose every day.

Antiretroviral therapy is quickly changing, with newer drug agents offering fewer side effects, greater durability, and a decreased risk of drug resistance. In the past, antiretroviral therapy was described as a three-drug “cocktail.” Today, with improved pharmacokinetics and a longer drug half-life, antiretroviral therapy may involve as few as two co-formulated drug agents.

Entry/Attachment Inhibitors

As per their name, entry/attachment inhibitors work by blocking the virus’s ability to attach to or enter healthy host cells. They do so by binding to different receptors on the surface of the host cell that HIV uses to lock onto and/or enter the cell. Without the means to enter a cell, HIV cannot replicate.

While several new antiretroviral drugs have been added to the treatment arsenal since 2010, older ones like Crixivan (indinavir), Invirase (saquinavir), Rescriptor (delavirdine), Videx (didanosine), Viracept (nelfinavir), and Zerit (stavudine) have been discontinued and are no longer in use.

Integrase Inhibitors

Integrase inhibitors work by blocking the incorporation of HIV’s DNA into the host cell’s DNA, a process known as integration. They do so by inhibiting a viral enzyme known as integrase.

Nucleoside Reverse Transcriptase Inhibitors

In order for HIV to replicate, it uses an enzyme called reverse transcriptase to translate its viral RNA into double-stranded DNA, which is then integrated into the nucleus of the host cell to “hijack” its genetic machinery. By doing so, HIV can begin to churn out multiple copies of itself.

Nucleoside reverse transcriptase inhibitors (NRTIs) block the action of reverse transcriptase and so prevent the replication of the virus.

Non-Nucleoside Reverse Transcriptase Inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) also block reverse transcriptase but in a different way. Rather than attaching to viral DNA like NRTIs do, NNRTIs bind directly to the enzyme, blocking its action.

Protease Inhibitors

Protease inhibitors (PIs) work by blocking an enzyme known as protease. Once HIV takes over the genetic machinery of the host cell, it produces long-chain proteins that must be cut into smaller pieces (by protease) in order to be assembled into a new viral particle. By binding to protease, the long-chain proteins cannot be cut and new viral particles cannot be produced.

Pharmacokinetic Enhancers

Also called HIV boosters, these drugs are used to “boost” the concentration of protease inhibitors in the bloodstream. Without them, the concentration of the accompanying PI would quickly fall beneath the therapeutic level, providing the virus an opportunity to replicate.

Fixed-Dose Combination Drugs

Fixed-dose combination drugs reduce the daily pill burden a person with HIV may otherwise be faced with when undergoing antiretroviral therapy. Some FDC drugs are used with other antiretroviral agents. Others are entirely used on their own.

Of the 22 FDC drugs approved for use in the United States, 14 are all-in-one treatments taken once daily.

  • U.S. Department of Health and Human Services. FDA-approved HIV medications.
  • ViiV Healthcare. Cabenuva.
  • Soriano V, Fernandez-Montero JV, Benitez-Gutierrez L, et al. Dual antiretroviral therapy for HIV infection. Expert Opin Drug Saf. 2017;16(8):923-932. doi:10.1080/14740338.2017.1343300

By James Myhre & Dennis Sifris, MD

Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.

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