What Are Antiretrovirals?

How Combination Therapy Renders HIV Powerless

Truvada HIV drug therapy
Truvada (tenofovir + emtricitabine). Justin Sullivan/Getty Images

There can be no doubt that the drugs used to treat HIV have advanced incredibly over the past 20 years. What some may not realize is just how far antiretroviral drugs have improved 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 man newly infected with HIV was 17 years.

While the antiretroviral drugs of the time managed to slow the disease, drug resistance developed quickly and people would often find themselves with few, in any, treatment options after a few short years.

At the same time, the daily pill burden could be astonishing. In some cases, a person would be faced with 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 confirmed that the use of a triple-drug therapy could completely control the virus and stop the disease from progressing.

Within two short years, the introduction of combination therapy resulted in a startling 60 percent drop in HIV-related deaths and illnesses. This revelation ushered in what would come to be known as the age of HAART (highly active antiretroviral therapy).

Advances in Combination Therapy

While not without its 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 dosing requires as little as one pill per day.

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

How Antiretrovirals Work

Antiretroviral drugs don't work by actively killing the virus. Instead, they target and block different stages of the virus' life cycle. By doing so, the virus is unable to replicate and make copies of itself. If treatment continues uninterrupted, the viral population will drop to a point where it is considered undetectable.

Because the virus is not killed, it can re-emerge (rebound) if treatment is suddenly stopped. The same can happen if the drugs are not consistently as prescribed. Over time, inconsistent dosing can lead to the development of drug resistance and eventually treatment failure.

Classes of Antiretroviral Drugs

Combination HIV therapy works by blocking several of stages of the HIV life cycle at once. There are currently five classes of antiretroviral drug, each classified by the stage of the life cycle they inhibit:

All told, there are 39 different antiretroviral drugs approved by the U.S. Food and Drug Administration, including 12 fixed-dose combination drugs (FDC) which contain two or more drugs.

Newer, more advanced drugs are being developed which would reduce triple-drugs down to two drugs.

Other formulations may soon allow for once-monthly or once-quarterly injections rather than daily pills.

Why Combination Therapy Works

When used in combination, antiretroviral drugs function like a biochemical tag team able to effectively suppress the multitude of viral mutations that can exist within an HIV population. If drug A is unable to suppress a certain mutation, then drug B and C can usually do the trick.

Genetic resistance testing provides doctors the tools need to identify the resistant mutations before treatment is started, By doing so, the doctor can tailor treatment by picking the drugs most able to suppress those mutations.

By keeping the viral population fully suppressed, not only do the drugs work longer, there are generally fewer side effects.

Antiretrovirals can also be used to lower the risk of HIV transmission from mother to child, to avert infection after an accidental exposure, or help an HIV-negative person avoid getting infected.

Sources:

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.

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.

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.

U.S. 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