How Antiretroviral Therapy Works for HIV

The human immunodeficiency virus (HIV) is a sexually transmitted infection (STI) that can also be spread by contact with infected blood or from mother to child during pregnancy, childbirth, or breastfeeding. Currently, around 38 million people live with HIV worldwide, of which an estimated 1.2 million reside in the United States.

Without treatment, it takes an average of eight to 10 years before HIV weakens your immune system to the point that you have acquired immunodeficiency syndrome (AIDS), the most advanced stage of infection.

While HIV cannot be cured, it can be treated with a group of drugs known as antiretrovirals. When used in combination, antiretroviral drugs prevent the virus from making copies of itself. By doing so, the virus can be suppressed to levels where it can do the body little harm. This article will discuss how antiretrovirals work to help people with HIV.

What Is Antiretroviral Therapy?

Antiretroviral therapy (ART) involves using two or more antiretroviral drugs to suppress the virus to undetectable levels in the blood. This treatment can slow the progression of the disease to a point at which you can live a long, healthy life.

The benefits of an undetectable viral load are threefold:

• With early ART, a person with HIV can expect to live a normal to near-normal life expectancy.
• Early ART reduces the risk of serious HIV-associated and non-HIV-associated illnesses by 72%.
• By sustaining an undetectable viral load, the risk of passing HIV to another person via sex is reduced to zero.

How It Works

Antiretroviral drugs do not kill HIV. Rather, they prevent the virus from making copies of itself by blocking stages in the virus's life cycle (also known as the replication cycle). Antiretrovirals are so named because HIV is a type of virus known as a retrovirus.

The different classes of antiretrovirals are named after the specific stage of the replication cycle they inhibit (block). The five broad categories are:

• Capsid inhibitors interfere with the HIV capsid, a protein shell that protects HIV's genetic material and enzymes needed for replication.
• Entry/attachment inhibitors prevent HIV from attaching to and entering host cells.
• Nucleoside reverse transcriptase inhibitors (NRTIs) prevent viral RNA from being translated into the DNA coding used to "hijack" a host cell.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) also block the translation of RNA into DNA in a different way.
• Integrase inhibitors (INSTIs) prevent the integration of DNA coding into the nucleus of a host cell.
• Protease inhibitors (PIs) prevent the chopping up of proteins used to build HIV copies.

There are also pharmacokinetic enhancers used in ART that boost the concentration of antiretrovirals so that they remain effective for a longer period of time, even if you miss a dose.

To fully suppress HIV to undetectable levels, two or more antiretroviral drugs must be used in combination therapy. To date, there is no single antiretroviral drug that alone can fully and durably suppress HIV.

Antiretroviral drugs need to be taken daily to maintain a consistent, suppressive level of medications in the bloodstream. In 2021, a new injectable drug, called Cabenuva (cabotegravir + rilpivirine), was introduced that requires two injections monthly or every two months to achieve the same level of viral control.

Drugs List

As of 2022, there are 26 individual antiretroviral agents approved for the treatment of HIV. Many are formulated into fixed-dose combination (FDC) drugs comprised of two or more antiretrovirals.

FDC drugs are attractive because they offer greater ease of use. There are currently 22 FDC drugs approved for the treatment of HIV, some of which only require one pill daily to achieve viral control.

Side Effects

While all drugs can cause side effects, current antiretrovirals tend to cause far fewer side effects than drugs of the past. Even so, side effects can occur and, in rare cases, be severe.

Short-term side effects may include headache, fatigue, nausea, diarrhea, insomnia, and even a mild rash. These tend to resolve within a few weeks as your body adapts to treatment.

Other side effects may be more severe. Some can occur soon after treatment is started or develop weeks or months later. The side effects can vary by the drug class and, in some cases, by the individual drug.

Among the concerns:

• Acute kidney failure has been known to occur with tenofovir DF, tenofovir AF, and ibalizumab, typically in people with underlying kidney disease.
• Central nervous system (CNS) disturbances like dizziness, abnormal dreams, loss of balance, and disorientation are associated with efavirenz but may occur with other NNRTIs like nevirapine and rilpivirine.
• Drug hypersensitivity is possible with all antiretroviral drugs but is more common (and potentially more severe) with abacavir and maraviroc.
• Lactic acidosis, the rare but potentially deadly buildup of lactic acid in the bloodstream, is most commonly associated with older NRTIs like stavudine (D4T), didanosine (DDI), zalcitabine (DDC), and zidovudine (AZT), but can occur with other antiretrovirals as well.
• Lipodystrophy is fat-related side effects. These include lipoatrophy, which is the loss of fat most related with older NRTIs, and disproportionate fat accumulation, which was most associated with older generations of protease inhibitors.
  
• Liver toxicity is possible with efavirenz nevirapine, maraviroc, zidovudine, and all PIs. People with underlying liver disease are at the greatest risk.
• Peripheral neuropathy, a sometimes-severe pins-and-needles sensation involving the hands or feet, can occur with the long-term use of zidovudine.

Tests

Once you have been diagnosed with HIV, your doctor will advise to you start treatment immediately to bring the virus under control. You will not only be counseled on how to take your drugs correctly (including dietary restrictions) but also advised on ways to maintain optimal adherence.

You will also be given baseline blood tests, called a CD4 count and viral load, against which your response to treatment will be measured. You will be asked to return every three to six months to have these blood tests repeated.

CD4 Count

The CD4 count measures the number of CD4 T-cells in your blood. CD4 T-cells are responsible for instigating the immune response and are the very cells that HIV targets for infection. As HIV kills off more and more of these cells, the body becomes less able to defend itself against otherwise harmless opportunistic infections.

The CD4 count measures the status of your immune system based on the number of CD4 T-cells in a cubic millimeter (cells/mm3) of blood. A CD4 count is broadly categorized as follows:

• Normal: 500 cells/mm3 or above
• Immune suppression: 200 to 499 cells/mm3
• AIDS: Under 200 cells/mm3

With early ART, the CD4 count should increase to normal to near-normal levels. People who delay treatment until the disease is advanced generally have a harder time rebuilding their immune system.

Viral Load

The viral load measures the actual number of viruses in a sample of blood. The viral load can run well into the millions if left untreated. If treated appropriately, the viral load can be reduced to undetectable levels.

Undetectable does not mean that the virus is gone. Although the virus may not be detectable with blood tests, there will be many hidden in the tissues throughout the body known as viral reservoirs. If ART is stopped, these latent viruses can reactivate and lead to a rebound in the viral load.

The viral load can also help determine if a treatment is failing due to drug resistance. Drug resistance most often occurs when you don't take your drugs as prescribed. But it can also develop naturally after many years of treatment. If drug resistance occurs, the viral load will gradually creep up even if you are taking your drugs as prescribed.

When the viral load indicates that a treatment has failed, your doctor will begin the process of selecting a new combination of drugs for you.

Other Treatments

There are no other medications other than antiretrovirals that can control HIV.

Even so, there are drugs a doctor may prescribe along with ART if you are at risk of an opportunistic infection. These preventive medications, referred to a prophylactics, are commonly prescribed when your CD4 count is below 200 or 100.

These may include daily oral antibiotics to prevent severe infections like pneumocystis pneumonia (PCP) or mycobacterium avium complex (MAC).

Healthy lifestyle practices are also advised, irrespective of your CD4 count. This helps reduce the risk of non-HIV-associated illnesses—such as heart disease and certain cancers—that occur earlier and more frequently in people with HIV.

Healthy lifestyle choices for people with HIV include:

• Eating a balanced diet low in saturated fats and sugar
• Maintaining a healthy weight
• Exercising regularly
• Keeping your blood pressure and cholesterol under control
  
• Getting the recommended vaccination
• Getting the recommended cancer screenings
• Quitting cigarettes
  

Talk to Your Doctor

The choice of ART relies heavily on the results of a genetic resistance testthat helps determine which antiretrovirals work best based on your virus's genetic profile. But it is not the sole factor involved in the selection of ART.

As you will be the one taking the pills every day, you will want medications with the greatest tolerability and the greatest ease of use. Both help improve adherence.

Let your doctor know if you have side effects that persist or worsen. Similarly, if you frequently miss doses, don't appease your doctor by telling them otherwise. It is far better to be honest and let your doctor know about any troubles you are experiencing. Often, treatment can be changed or simplified.

With that said, never stop treatment without first speaking with your doctor.

Summary

Antiretroviral therapy is used to control HIV. It relies on drugs that inhibit points of the viral replication cycle so the virus cannot make copies of itself and infect immune system cells. Antiretroviral drugs are usually given daily in the form of a pill, which may contain a combination of drugs. These medications may have side effects.

The drugs used in antiretroviral therapy are often determined by genetic resistance testing for the virus variant seen in the individual. Tests that monitor the effectiveness of antiretroviral therapy include the CD4 count and the viral load.

If an individual isn't responding to antiretroviral therapy or isn't able to adhere to taking the medications, another drug combination may be used.

A Word From Verywell

Antiretroviral therapy has advanced to where people living with HIV enjoy long, healthy lives with minimal side effects or impact on lifestyle. With that said, the drugs only work if you take them, and that is where many people fall short.

According to the Department of Health and Human Services (HHS), fewer than 60% of people living with HIV in the United States achieve and sustain an undetectable viral load. Moreover, of the estimated 1.2 million people living with the disease in the United States, roughly 1 in 7 remain undiagnosed.

If you have trouble paying for your medications or doctor's visits, some programs can help. These include co-pay and patient assistance programs that can reduce your out-of-pocket costs to zero.

There are also federally funded programs under the Ryan White Act that can assist with medications and other costs of care. Speak with your doctor or a certified social worker experienced with HIV.