An Overview of HIV Treatment

There can be no doubt that the drugs used for the treatment of HIV have advanced incredibly over the past decade. This is certainly true when compared to older generation agents that had higher rates of toxicity and were more prone to the early development of drug resistance. What some may not realize is just how far the science has come since 1996, when the first triple-drug therapy changed the very course of the pandemic.

Prior to 1996, the average life expectancy for a newly infected 20-year-old male in the U.S. was a mere 17 years. Today, newer generation therapies are able to afford life spans equal to that of the general population while boasting far fewer drug side effects and offering dosing schedules as simple as one pill per day.

Yet, despite these advances, less than half of Americans receiving treatment are able to achieve the goals of therapy, due mainly to inconsistent dosing or voluntary treatment interruptions. More concerning yet is the fact that, of the 1.2 million Americans living with HIV today, anywhere between 20 to 25 percent have yet to be diagnosed.

Ultimately, the treatment of HIV is about more than just pills. It's about understanding how the drugs work and identifying what you need to do as an individual to achieve the best positive results, whether you are newly infected or re-engaging with care.

What Are Antiretroviral Drugs?

HIV is classified as a retrovirus, meaning that it replicates in reverse to how other viruses replicate. Rather than transcribing its genetic code from DNA to RNA like most living organisms, HIV transcribes its code from RNA to DNA.

By identifying the mechanisms by which HIV replicates, scientists developed drugs that are able to interrupt specific stages in the virus’ life cycle. These drugs, which we refer to as antiretrovirals, are used in combination therapies to suppress viral replication to a point where it is considered undetectable.

While highly effective, antiretroviral drugs do not eradicate the virus but rather impede its ability to replicate. By doing so, the immune system remains intact and is better able to fight diseases (known as opportunistic infections) that can arise if immune defenses are compromised.

How Do Antiretrovirals Work?

Antiretroviral therapy works by preventing HIV from replicating at key stages in its life cycle, broadly defined as:

  1. Attachment–the stage where HIV attaches itself to a host cell
  2. Fusion–the stage where HIV fuses to the cellular membrane and deposits its genetic material into the host cell
  3. Reverse transcription–the stage where the viral RNA is transcribed into DNA
  4. Integration–the stage where the HIV’s DNA is integrated into the host cell’s nucleus (using the integrase enzyme), effectively hijacking the genetic machinery
  5. Transcription–the stage when HIV uses that machinery to create the building blocks for new viruses
  6. Assembly–the stage where an immature virus is assembled and moved toward the surface of the host cell
  7. Budding and maturation–the stage where the virus literally buds from the host cell using the protease enzyme to create a fully mature virus

By using a combination of drugs (which inhibit two or more stages of the life cycle), HIV’s ability to replicate is almost completely stopped, with only a few mutant viruses able to escape and circulate freely in the blood stream.

Classes of Antiretroviral Drugs

There are currently five classes of antiretroviral drug, each classified by the stage of the life cycle they inhibit:

  1. Fusion inhibitors
  2. Nucleoside reverse transcriptase inhibitors
  3. Non-nucleoside reverse transcriptase inhibitors
  4. Integrase inhibitors
  5. Protease inhibitors

Of these five classes, there are 39 different antiretroviral drugs approved by the U.S. Food and Drug Administration, including 12 fixed dose combinations (FDC) that contain two or more drugs.

Why Combination Therapy Works

HIV is typically composed of a primary viral type (called the "wild type" virus) as well as a plethora of viral mutations, each with unique genetic signatures and conformations. Combination therapy is used to suppress as many of these variants as possible to a point where a person’s viral load is considered undetectable.

When used in combination, antiretroviral drugs function as something of a biochemical "tag team." If drug A, for example, is unable to suppress a variant by supressing a stage in the life cycle, then drug B and C can usually complete the job by attacking a different stage.

Genetic resistance testing is used by doctors to help identify the types and degrees of mutations that exist within your viral population. Based on the test results, treatment can be tailored so that the drugs prescribed can not only affect complete viral control but also overcome any drug resistant mutations that may exist within the viral population.

When to Start Antiretroviral Therapy

In May 2014, the U.S. Department of Health and Human Services (DHHS) revised its HIV treatment guidelines, recommending the implementation of therapy in all adults diagnosed with HIV, irrespective of CD4 counts or stage of disease. In the past, treatment was only recommended when a person's CD4 count dropped below the threshold of 500 cells/mL.

The DHHS decision was supported by evidence that early treatment is associated with a number of positive outcomes, namely:

  • A reduction in the risk of illnesses associated with HIV infection
  • A reduction in the risk of transmission from mother to child
  • A reduction in the risk of HIV transmission

The latter recommendation is further supported by evidence that antiretroviral therapy can significantly reduce the infectivity of a person living with HIV, a strategy known as Treatment as Prevention (or TasP). It has also been shown that people who are provided with early HIV therapy are 53 percent less likely to develop serious illness, both HIV- and non HIV-related.

By contrast, deferring treatment until a person’s CD4 count drops below 200 (the stage of disease known as AIDS) can reduce that person's life expectancy by an average of 15 years.

What Drugs Should I Start With?

While treatment guidelines will regularly change and evolve with the release of new drugs or scientific information, the current body of science advocates the use of newer generation integrase inhibitors and nucleoside analogues in first line therapy.

The aim of first line therapy is to prescribe the drugs that will provide the simplest dosing schedule, the fewest side effects, and lowest risk for the development of drug resistance. Today, many of the drug combinations are available in a single pill, once daily formulation, which can significantly enhance a person’s ability to maintain the levels of adherence that are key to treatment success.

This is particularly important as the current body of research suggests that people on treatment need to maintain greater than 90 percent adherence in order to achieve the optimal goals of therapy.

Learn more about the current treatment recommendations issued by the U.S. Department of Health and Human Services for adults living with HIV.

What Happens If a Treatment Fails?

If taken as prescribed, your antiretroviral drugs should remain wholly effective for five, 10, or even 15 years. This can differ from person to person, of course, depending on the types of virus one is infected with. But generally speaking, the duration of treatment efficacy is directly associated with the rate of adherence a person is able to achieve.

Failure to sustain viral control allows the virus to replicate freely, giving drug resistant mutations the ability to thrive and become the predominant variant. When this happens, treatment will become less and less effective and eventually stop working altogether. This is known as treatment failure.

At this stage, doctors will need to perform genetic resistant testing to identify how extensive the drug resistance is. In some cases, resistance may affect only one or two drugs; in others, entire classes may be rendered ineffective. Treatment will then need to be revised to better overcome these issues while addressing the adherence barriers that may have caused the treatment failure in the first place.

Learn more about the tips and tricks for maintaining optimal adherence to HIV therapy.

Why Can’t Antitretrovirals Cure HIV?

While antiretrovirals are able to suppress viral replication, they primarily do so with the virus freely circulating in body fluids.

Within the viral population, a subset of the virus, called provirus, is able to embed itself in cells and tissues of the body known as latent reservoirs. Rather than replicating and emerging from infected cells, proviral HIV divides and replicates along with the host cell, undetected by the immune system. It can remain in this state for years and even decades, only to re-emerge when either treatment is stopped or proves ineffective.

Until scientists are able to "kick" the virus out of these hidden reservoirs, the ability of any agent to entirely eradicate HIV is unlikely, if not impossible.

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