Antiretroviral Therapy

What is antiretroviral therapy (ART)?

Antiretroviral therapy (ART) is a combination of medications that treat HIV. HIV (human immunodeficiency virus) is a virus that destroys CD4 cells (also called helper T-cells), an important part of your immune system. Without the protection of CD4 cells, you’re more likely to get life-threatening infections.

While ART can’t cure HIV, it can reduce the levels of HIV in your body. Low levels of the virus mean your body can produce more CD4 cells. This keeps your immune system healthy and makes you less likely to get serious infections.

ART medications use a variety of ways to stop HIV from getting into your cells and reproducing. You usually take a combination of two to four medications that work in different ways to reduce the levels of virus (also called viral load) in your body. Taking a combination of medications, rather than just one, makes the treatment more effective and reduces the risk that it’ll stop working. If your viral load is low enough, tests won’t be able to detect HIV in your blood (undetectable levels).

HIV treatment is called “antiretroviral” because HIV is a retrovirus. This means it uses its genetic instructions (RNA) as a template to make DNA (most of the time, in human cells, DNA is used to make RNA). You might hear antiretroviral therapy called ART, cART (combined antiretroviral therapy) or HAART (highly active antiretroviral therapy) — they all mean the same thing.

What does it mean to have “undetectable” HIV levels?

If you have undetectable levels of HIV — also called viral suppression — it means viral load tests (tests that measure how much HIV is in your body) can’t detect HIV in your blood. For most tests, this means you have fewer than 20 copies of HIV per milliliter of blood (< 20 copies/mL).

“Undetectable” doesn’t mean you’re cured of HIV. HIV can hide in your body and come back if you stop taking medications to keep it in check. You’ll still test positive on HIV tests (which look for HIV antibodies, not the virus itself). But people who consistently have undetectable viral loads can live as long as people who don’t have HIV. And studies show that you can’t spread HIV to others through sex if you have undetectable levels of the virus.

How do you take antiretroviral therapy?

Most people take ART in pill form. You might take one pill with a combination of medications or a few different pills. Some medications also come in a liquid form that you swallow.

Some people can get their medication in an injection (shot) instead of a pill. A healthcare provider gives you a shot once a month or every two months. You might be eligible to get the shot if you:

• Have an undetectable viral load.
• Have never had treatment stop working in the past.
• Aren’t allergic to the ingredients in the shot.

How does antiretroviral therapy work?

Each ART medication stops HIV at a different part of the virus’s replication (copying) process. To understand how antiretroviral therapy works, it’s important to understand how HIV infects your cells and multiplies — it’s a bit like someone breaking into your house and reprogramming your security system so other intruders can get in.

HIV gets inside your cells, writes instructions for making more copies of itself and uses your cells’ tools to make those copies. It destroys your T-cells in the process, preventing you from being able to fight off other infectious diseases.

The specific steps include:

1. Attachment (binding). HIV uses a protein (GP120) to attach to receptors on your CD4 cells (immune cells). Receptors are like locks HIV must open to enter your cells. This is a multistep process that involves the protein changing shape and locking on to more than one receptor.
2. Fusion. The outer coating (membrane) of HIV joins with the CD4 cell — this is called fusion.
3. Entry. The capsid (HIV’s “toolbox” — a shell made of proteins carrying its genetic material and tools it needs to replicate) gets inside.
4. Reverse transcription. Reverse transcriptase, an enzyme HIV carries, makes DNA (the instructions your genes are written in) from RNA (the instructions it carries with it to make more copies of the virus). It builds the DNA from building blocks found inside your cells (nucleosides).
5. Integration. HIV DNA gets into the nucleus of the cell, where your DNA lives. There, the enzyme integrase inserts the HIV DNA into your DNA. From there, your cells read the virus’s DNA as if it were your own body’s instructions.
6. Transcription. Your cell codes its DNA and HIV’s DNA into messenger RNA (mRNA).
7. Translation. The mRNA moves outside of the nucleus and uses your cell’s ribosomes (similar to tiny factories that make proteins) to create proteins from its instructions. Proteins are a part of your body that perform specific functions.
8. Assembly. HIV protease breaks these proteins apart and packages them into more viruses to infect other cells.
9. Budding and cell death. The CD4 cell is destroyed when the viruses escape the cell to infect more cells.

Which drugs are used in antiretroviral therapy?

There are many different types of antiretroviral medications. Each one uses a different strategy, at different points in HIV replication, to stop HIV from making more copies of itself. Types of ART medications include:

• Entry inhibitors. These include attachment inhibitors, fusion inhibitors, CCR5 antagonists and post-attachment inhibitors.
• Capsid inhibitors.
• Nucleoside reverse transcriptase inhibitors (NRTIs).
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
• Integrase inhibitors/integrase strand transfer inhibitors (INSTIs).
• Protease inhibitors.
• Pharmacokinetic enhancers.
• Combination medications.

Many ART medications, like NRTIs, NNRTIs and INSTIs, work by breaking or preventing HIV’s tools (enzymes) from working. Others work in different ways.

Capsid inhibitors

HIV’s capsid core holds its replication instructions (RNA) and enzymes that HIV uses as tools in the replication process. For HIV to reproduce, the proteins making up the capsid need to:

• Be able to come apart or open somehow to get enzymes and RNA out.
• Be flexible enough to get into a small opening in the nucleus.
• Be assembled into new virus capsid cores.

Capsid inhibitors bind together the proteins that make up the capsid — like putting a padlock on its toolbox. This prevents it from being flexible enough to get into the nucleus and makes it harder for it to disassemble and assemble into new cores. Lenacapavir (Sunlenca®) is the only U.S. Food and Drug Administration (FDA)-approved capsid inhibitor.

Nucleoside reverse transcriptase inhibitors (NRTIs)

HIV creates DNA by using building blocks (nucleosides) that exist inside your T-cells. It uses the enzyme reverse transcriptase to string the nucleosides together. NRTIs trick reverse transcriptase by using “decoy” nucleosides that don’t work.

These fake building blocks look like the real thing. But when the enzyme adds them to the DNA string, it prevents it from adding any other (real) building blocks to complete the string.

NRTIs are some of the most common medications used to treat HIV. Examples include:

• Abacavir/ABC (Ziagen®).
• Emtricitabine/FTC (Emtriva®).
• Lamivudine/3TC (Epivir®).
• Tenofovir disoproxil fumarate/TDF (Viread®).
• Tenofovir alafenamide/TAF.
• Zidovudine/AZT/ZDV (Retrovir®).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Rather than giving the virus fake building blocks to make DNA with, NNRTIs attach to reverse transcriptase itself. This prevents it from working. NNRTIs include:

• Doravirine/DOR (Pifeltro™).
• Efavirenz/EFV (Sustiva®).
• Etravirine/ETR (Intelence®).
• Nevirapine/NVP (Viramune®,Viramune XR®).
• Rilpivirine/RPV (Edurant®).

Integrase inhibitors/Integrase strand transfer inhibitors (INSTIs)

If HIV is successful in making DNA from its RNA, it will bring its DNA into your cell’s nucleus (the part of the cell that contains human DNA). Integrase will insert the HIV DNA into your DNA. INTSIs attach to integrase and prevent it from working. INSTIs include:

• Bictegravir/BIC (only available in combination medications).
• Cabotegravir/CAB (Vocabria®).
• Dolutegravir/DTG (Tivicay™).
• Elvitegravir/EVG (only available in combination medications).
• Raltegravir/RAL (Isentress®, Isentress HD®).

Protease inhibitors

In order for HIV to go on to infect more cells, it needs to break apart proteins and package them up into new copies of the virus. An enzyme called protease does this job. Protease inhibitors block protease so it can’t cut proteins into their active pieces. Protease inhibitors include:

• Atazanavir/ATV (Reyataz®).
• Darunavir/DRV (Prezista®).

Pharmacokinetic enhancers

Pharmacokinetic enhancers, or “boosters,” are medications that help other medications work better. They slow down how quickly your body breaks down other medications, giving them more time to work. These agents are used with protease inhibitors, like atazanavir and darunavir, or elvitegravir, which is an integrase inhibitor. Pharmacokinetic enhancers for HIV treatments include:

• Cobicistat/COBI (Tybost®).
• Ritonavir/RTV (Norvir®). RTV was first developed for use on its own but is now most commonly used to boost other antiviral medications.

Combination HIV medicines

Many ART medications come in combinations of two or three drugs together. Most commonly, they’re two NRTIs (called the “backbone”) combined with another type of ART medication (usually an INSTI or NNRTI, or sometimes a PI and a booster). There are many combination ART medications. Some common examples include:

• Biktarvy® (BIC/FTC/TAF).
• Triumeq® (ABC/DTG/3TC).
• Dovato (DTG/3TC).
• Symtuza (DRV/COBI/FTC/TAF).

Entry inhibitors

Entry inhibitor drugs use many different methods to prevent HIV from attaching to and entering your cells. These methods are a bit like gumming up your door locks or blocking the keyhole so the virus can’t get into your house. These agents aren’t prescribed very often. They’re usually reserved for treatment of an HIV virus that’s resistant to other antiretrovirals. They include:

• Attachment inhibitors. Attachment inhibitors block the GP120 protein on HIV from attaching to CD4 receptors. Fostemsavir/FTR (Rukobia®) is an attachment inhibitor.
• Post-attachment inhibitors. These drugs prevent GP120 from changing its shape and attaching to additional receptors to help it get inside CD4 cells. You can think of it like getting the key in the lock but not being able to turn it. Ibalizumab/IBA (Trogarzo®) is a post-attachment inhibitor.
• CCR5 Antagonists. CCR5 is a protein on CD4 cells that some forms of HIV (but not all) attach to in order to get inside the cells. CCR5 antagonists block the protein so HIV can’t get inside. Maraviroc/MVC (Selzentry®) is a CCR5 antagonist.
• Fusion inhibitors. These medications bind to GP41 proteins on the virus to block HIV from merging with and entering CD4 cells. Enfuvirtide/T20 (Fuzeon®) is a fusion inhibitor.

Which ART medications are right for me?

Your provider will recommend medications based on:

• How high your viral load and CD4 counts are before starting treatment.
• Whether you’ve been treated with ART medications before. This includes pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).
• Results of testing for medication resistance.
• Whether you’re pregnant or plan to become pregnant.
• Whether your partner has HIV.
• How well you can stick to your medication schedule.
• Dietary considerations (some medications need to be taken with or without food).
• Other health conditions you have or medications you take.

ART and other medical conditions

Additional health conditions or medications you take can affect how well certain ART medications work or increase your risk for side effects or complications. Talk to your provider about medications you take or health conditions you have, including:

• Chronic kidney disease.
• Hepatitis B.
• Hepatitis C.
• Tuberculosis.
• Liver cirrhosis.
• Osteoporosis.
• High cholesterol (hyperlipidemia).
• Psychiatric illnesses.
• Dementia.
• Heart conditions.
• Tuberculosis.
• Medications or conditions that may prolong QT (when your heart’s electrical system takes longer than usual between beats).

When should I start antiretroviral therapy?

Anyone with HIV should get started on ART as soon as possible. Even if your CD4 counts are high, studies suggest that treatment is most successful when you start early, rather than waiting for your counts to drop.

How long do you have to be on antiretroviral therapy?

You’ll need to take antiretroviral medications for the rest of your life. If you regularly miss doses (for example, one or more doses per week), the virus can start to multiply again and may become harder to treat. Studies suggest that people who miss doses of ART are more likely to:

• Have lower T-cell counts.
• Have higher viral loads.
• Develop resistance to medications (they no longer work to suppress HIV).
• Get life-threatening infections.

What are the benefits of antiretroviral therapy?

Taking multiple medications together reduces the risk that HIV will develop resistance to the treatment — this causes medications to stop being effective. And while ART can’t cure HIV, consistently taking ART medications can reduce your viral load to low or even undetectable levels. This:

• Keeps your T-cell counts higher and your immune system healthy.
• Lowers your risk of having a weakened immune system (immunocompromised) and developing serious or fatal infections.
• Lowers your risk of developing certain cancers that are more common among people with HIV (like Kaposi sarcoma, non-Hodgkin lymphoma and others).
• Lowers the risk you’ll develop AIDS.
• Prevents HIV from spreading to others through sex if you have an undetectable viral load.

How well does antiretroviral therapy work?

When taken correctly and consistently, ART is very successful. Studies suggest that over 90% of people (9 out of 10 people) who take ART medications as prescribed (called “treatment adherence”) have undetectable levels of HIV in their blood within 12 months. Most people who start ART soon after their diagnosis and stay on it can expect to live as long as someone without HIV. Without treatment, someone with HIV is expected to live eight to 10 years.

What are the risks of ART?

The biggest risks of ART are:

• Not being able to take medications consistently. If you often miss doses of your medication, HIV can multiply again, weaken your immune system, and potentially become resistant to medications.
• Having, allergic or hypersensitivity reactions
• Side effects.

Side effects of ART

Side effects of ART therapy depend on which medications you’re taking. Side effects and complications could include:

• Nausea.
• Vomiting.
• Diarrhea.
• Mood changes or depression.
• Difficulty sleeping.
• Dry mouth.
• Weight gain.
• Headache.
• Rash.
• Dizziness.
• Tiredness (fatigue).
• Pain or soreness at the injection site of shots.
• High cholesterol, which can lead to heart disease.
• Long QT syndrome.

Many of these side effects are temporary and will only last a few weeks, until your body gets used to the medications. Other side effects, like high cholesterol, can have long-lasting health effects.

How long will it take for me to reach undetectable levels of HIV?

For most people, ART reduces HIV levels within six months, and even as soon as one to two months after starting. Your provider usually checks your virus levels every four to eight weeks when you start ART. If your viral loads are consistently reduced below detectable levels for six months of treatment, your viral loads are undetectable. This means you can’t spread HIV to others through sex. If your viral loads stay undetectable, you’re likely to live as long as someone without HIV.

Monitoring

Your healthcare provider will monitor your viral load and CD4 counts to see how well you’re responding to treatment. Your provider will check your viral levels:

• Before you start treatment.
• Every four to eight weeks when you start treatment, until you reach an undetectable viral load.
• Every three to four months for at least two years after you reach an undetectable viral load.
• Every six months if your provider feels like treatment is keeping your viral load consistently low.
• More often (usually every four to eight weeks) if you change treatment, if your viral load increases, or if you have a change in other medications or your health.

Your provider will check your CD4 count:

• Before you start treatment.
• Three months after starting treatment.
• Every three to six months during the first two years of treatment, depending on your levels of CD4.
• Every six to 12 months, depending on your levels, if your CD4 counts are stable after two years of treatment.
• Optionally if your CD4 counts are consistently above 500 cells/mm3 after two years of treatment.

Why do I need to continue ART if I don’t have detectable levels of HIV?

It’s important to remember that ART doesn’t entirely eliminate HIV in your body. It only works on viruses that are actively entering your cells and reproducing. HIV is “invisible” to these medications if it’s inside your cells and not actively making more copies of itself. ART can stop HIV from reproducing, bringing it to levels so low that blood tests can’t detect it. But if you stop taking ART when you reach undetectable levels, the hidden virus can become active again. It might be resistant to medication and harder to treat if it comes back.

When should I call my healthcare provider?

Talk to your provider if you have trouble taking your medication as prescribed or if you’re experiencing intolerable side effects. They might be able to adjust your medications to make treatment easier. They can also help you develop strategies for managing your schedule or side effects.