Antiretrovirals Overview

How Combination Therapy Renders HIV Powerless

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There can be little doubt that the drugs used to treat HIV have advanced enormously over the past 25 years. What some may not realize is just how much antiretroviral therapy has improved since 1996, when the first triple-drug therapy changed the very course of the AIDS pandemic.

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A Short History of Antiretroviral Therapy

Prior to 1996, the average life expectancy of a 20-year-old man newly infected with HIV was a mere 19 years. While the antiretroviral drugs of the time managed to slow the progression of the disease, drug resistance developed quickly, and people would often find themselves with few if 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 at 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 remarkable 60% drop in HIV-related deaths. This revelation ushered in what would come to be known as the age of HAART (highly active antiretroviral therapy).

Advances in Treatment

While not without its challenges, modern antiretroviral therapy has advanced to a point where drug toxicities are a mere shadow of what they used to be. Drug resistance takes far longer to develop, while dosing requires as few as one pill per day.

There is now even an injectable option, called Cabenuva (cabotegravir + rilpivirine), that requires two shots once monthly rather than having to take pills every day.

Most importantly, with optimal treatment, a person newly infected with HIV can expect to enjoy a normal to near-normal life expectancy. According to research published in the Journal of Acquired Immune Deficiency Syndrome, a 20-year-old who tests positive for HIV today could very well live into their 70s and beyond.

Goals of Therapy

Antiretroviral drugs do not kill the virus; rather, they block different stages of the virus's life cycle. By doing so, the virus is unable to replicate and make copies of itself. If treatment continues without interruption, the viral population will drop to a point where it is undetectable (meaning not zero but below the level of detection with current testing technologies).

Although the virus can be fully suppressed with antiretroviral therapy, it can still embed itself in tissues throughout the body, called latent reservoirs, and rebound if treatment is stopped.

Moreover, if the drugs are taken irregularly or not taken as prescribed, drug-resistant mutations can develop. If adherence is not corrected, the resistant mutations can build, one atop the next, eventually leading to treatment failure.

On the other hand, if the virus is fully suppressed and remains undetectable, a person with HIV has a "effectively zero" chance of passing the virus to others, according to a landmark study published in May 2019 in The Lancet.

Drug Classes

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

  • Entry/attachment inhibitors
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors
  • Integrase inhibitors
  • Pharmacokinetic enhancers ("boosters")

As of January 2021, there were 48 different HIV drugs approved by the Food and Drug Administration, including 22 fixed-dose combination drugs that contain two or more antiretroviral agents.

How Antiretroviral Therapy Works

HIV causes disease by depleting immune cells, called CD4 T-cells, that the body needs for an effective immune response. As their numbers are depleted, the body's ability to fight disease diminishes, leaving it vulnerable to an ever-widening range of opportunistic infections.

In order for HIV to replicate, it must go through various stages of its life cycle:

  1. Attach to and enter a host cell (entry/attachment)
  2. Translate its viral RNA into DNA (reverse transcriptase)
  3. Integrate its genetic coding into the host cell's nucleus (integration)
  4. Create the building blocks by which new viruses are formed (protease catalysis)
  5. Start churning out copies of itself (budding)

Once new viral particles are released, the cycle starts anew.

Antiretroviral drugs work by blocking different stages of this cycle. When used in combination, they function as a biochemical tag team—one that is able to suppress the multitude of viral mutations that can exist within a single HIV population.

If one antiretroviral drug is unable to suppress a certain mutation, the other one or two drugs usually can by blocking a different stage of the cycle.

To ensure you receive the right combination of drugs, doctors will perform genetic resistance testing and other tests to establish the characteristics of your virus and the number and types of resistant mutations you have. By doing so, the doctor can tailor your treatment by picking the drugs most able to suppress those mutations.

By starting treatment early when your immune system is still intact, the risk of severe HIV-associated and non-HIV-associated illness is decreased around 72%, according to a seminal 2015 study published in the New England Journal of Medicine.

A Word From Verywell

Antiretroviral drugs are one of the major scientific breakthroughs of modern medicine, transforming a disease that was once thought to be a death sentence into a chronically managed condition.

Even so, the drugs only work if you take them. And, this remains a serious challenge to public health officials. Today, roughly 15% of the 1.2 million Americans with HIV remain undiagnosed. Of those who are diagnosed, only 50% are retained in care and only 56% are virally suppressed.

By getting tested and treated, people with HIV can live long, healthy lives, keeping themselves and others safe from the risk of transmission.

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