What Are Antiretrovirals (and How Do They Work)?

Newer HIV Drugs Offer Easier Dosing, Fewer Side Effects

Photo Credit: Justin Sullivan/Getty Images

There is no doubt that the drugs used for the treatment of HIV have advanced incredibly over the past decade. What some may not realize is just how far the sciences have come since 1996, when the first triple-drug therapy changed the very course of the pandemic.

A Short History of Antiretroviral Therapy

Prior to 1996, the average life expectancy of a 20-year-old male newly infected with HIV was around 17 years.

While the antiretroviral drugs of that time managed to slow progression of the disease, treatment failure was usually high due to the speed by which drug resistance occurred.

At the same time, the daily pill burden could often be astonishing: sometimes 30 or more pills per day, often taken around the clock on four to six hour intervals.

Then, in 1995, a new class of drugs called protease inhibitors was introduced. Barely a year later, three different studies demonstrated that the use of a triple-drug therapy could suppress the virus to levels considered undetectable at the time.

Within two years, the introduction of this new practice resulted in a startling 60-80% reduction in HIV death and illness. With that revelation, the era of HAART (highly active antiretroviral therapy) was born.

Advances in Combination Therapy

While not without challenges, modern antiretroviral therapy has advanced to where drug toxicities are a mere shadow of what they used to be.

Drug resistance is generally slower to develop, while "pill burden" has virtually become an anachronism with the introduction of single-pill formulations like Atripla and Stribild.

Most importantly, a person newly infected with HIV can now expect to have a normal to near-normal life expectancy  According to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), a 20-year-old male infected today  could survive very well into his 70s, with proper treatment and medication adherence.

How Do Antiretrovirals Work?

Despite these advances, there are some who still equate antiretroviral use with chemotherapy. In chemotherapy (such as that used for cancer), the drugs specifically target the fast-replicating cells of the body, taking out both the "bad" cells and a number of "good" ones, as well.

By contrast, antiretroviral drugs work by preventing the virus from replicating during a specific stage in its life cycle. As such, they are not cytotoxic (toxic to cells) but rather impede a process essential to the reproduction of the virus itself.

As a rule, HIV cannot replicate unless it completes every stage of the HIV life cycle, namely:

  1. Fusion and Entry
  2. Reverse Transcription
  3. Integration
  4. Transcription and Translation
  5. Assembly
  6. Budding and Maturation

By inhibiting a stage in this process, the viral population can be completely suppressed, ensuring a person's immune function remains intact and strong.

Classes of Antiretroviral Drugs

Antiretrovirals works by effectively blocking one or several of stages of the HIV life cycle. There are currently five classes of antiretroviral drug, each classified by the stage of the life cycle they inhibit:

  • Nucleoside and nucleotide reverse transcriptase inhibitors
  • Non-nucleoside reverse transcriptase inhibitords
  • Integrase inhibitors
  • Protease inhibitors

All told, there are 39 different antiretroviral drugs approved by the FDA, including 12 fixed dose combinations (FDC) which contain two or more drugs.

Why Combination Therapy Works

When used in combination, the antiretrovirals act as something of a biochemical tag team" able to more effectively suppress the variety of resistant mutations that can develop in an HIV population. If drug A is unable to suppress a certain viral mutation, then drug B and C can usually complete the job.

Genetic resistance testing further enables doctors to identify the types and degree of viral resistance before treatment is started, ensuring  the best combination of antiretroviral drugs. By keeping the viral population fully suppressed, not only do the drugs not work longer but there are generally fewer side effects.

It has also been shown that the use of antiretrovirals can significantly reduce the risk of transmission from mother to child; after an accidental exposure (in a strategy known as post-exposure prophylaxis, or PEP); or in persons wanting to remain uninfected (pre-exposure prophylaxis, or PrEP). 


Wood, E; Low-Beer, S.; Bartholomew, K., et al. "Modern antiretroviral therapy improves life expectancy of gay and bisexual males in Vancouver's West End." Canadian Journal of Public Health. March 2000;91(2):125-8.

Hogg, R.; Samji, H.; Cescon, A., et al. "Temporal Changes in Life Expectancy of HIV+ Individuals: North America." 19th Conference on Retroviruses and Opportunistic Infections (CROI). March 7, 2013; Seattle; Oral Presentation #137.

Sax, P.; Meyers, J.; Mugavero, M., et al. "Adherence to Antiretroviral Treatment and Correlation with Risk of Hospitalization among Commercially Insured HIV Patients in the United States." Tenth International Congress on Drug Therapy in HIV Infection. November 8, 2010; Glasgow; Oral Presentation #0113.

Kitahata, M.; Gange, S.; Abraham, A., et al. "Effect of early versus deferred antiretroviral therapy for HIV on survival." New England Journal of Medicine. April 30, 2009; 360(18):1815-1826.

Department of Health and Human Services (DHHS). "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." Rockville, Maryland; updated July 14, 2016.

Continue Reading