As science advances in the fight against HIV, one thing remains clear - education is our greatest weapon. By learning how HIV lives and grows within the body, physicians can gain insight into its vulnerability. And when patients and their loved ones better understand the illness and how to fight it, they can take an active role in getting the healthcare they need and deserve - including the latest advances in highly effective antiviral drugs.

However, before you can fully understand how antivirals work to stop HIV, you must first learn about HIV. This information details what HIV is, how it reproduces, why antivirals work to stop it, and why they sometimes fail. You will also learn about drug resistance and why it is a significant obstacle to the long-term success of HIV therapy, also known as Highly Active Antiretroviral Therapy (HAART). By taking this inside look at HIV and drug resistance, you will learn how scientists are working to overcome drug resistance and how tools like resistance testing can help physicians design targeted treatment plans that are more likely to be effective for a longer period of time.

• What is HIV?
• How do antiviral medications treat HIV?
• What is treatment failure?
• What happens if someone's treatment fails?
• What causes treatment failure?
• What is drug resistance?
• How can someone's virus become resistant to his or her medications?
• What does cross resistance mean?
• How does drug resistance affect treatment options?
• Can resistance be prevented?

To better understand drug resistance and its effect on HIV treatment, it is important that you have a solid base of knowledge about what HIV is and what it does to the body. To start, the human immunodeficiency virus (HIV) is a retrovirus that infects CD4 T cells. CD4 T cells are important cells in the immune system that signal the body to fight off infection and disease.

Once HIV enters the body, it attaches itself to CD4 T cells and begins the replication process. Replication is how HIV makes copies of itself and multiplies. In order to replicate, an HIV particle must get its genetic blueprint, known as RNA, inside the host CD4 T cell. By doing this, the virus can reprogram the CD4 T cell and turn it into a virus making machine.

Once inside the host cell, the virus must translate the RNA instructions into DNA so that the cell can understand them. To do this, HIV uses an enzyme known as reverse transcriptase. This enzyme takes the single strand of viral RNA and turns it into a double strand of DNA, which the cell can read. A class of drugs known as reverse transcriptase inhibitors is designed to stop this process.

Once the new viral RNA strand moves out of the host DNA, the strand is "cut" into smaller subunits. The protease enzyme makes this process possible; however, drugs called protease inhibitors interrupt the enzyme's activity.

The subunits come together to form new HIV particles, which move out of the cell to infect other CD4 T cells. This process repeats itself continuously, and after repeated assaults by viral particles, the CD4 host cells die. As the number of CD4 cells decreases, the immune system can lose its ability to fight life-threatening infections.

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The goals of HIV therapy are to slow the growth of the virus and reduce the level of HIV in a person's body, known as the viral load. Currently, there are 15 antiviral drugs available for the treatment of HIV, with many more in clinical development. The approved drugs are divided into three classes: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

All three classes of antiviral drugs work by interrupting the process of HIV reproduction. Protease inhibitors block a part of HIV called protease, while NRTIs and NNRTIs block the reverse transcriptase enzyme. Each of these interruptions in the HIV replication process prevents the virus from infecting new cells.

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Treatment failure means that the drugs in a person's regimen are no longer working to suppress HIV replication and reduce the amount of virus in the body. Treatment failure can be defined clinically, immunologically, and virologically.

Clinical failure is when a person's HIV-related symptoms become worse, or when he or she develops an opportunistic infection. Immunologic failure means that the number of CD4 T cells in a person's body is greatly reduced.

Most physicians define treatment failure as virologic failure. Virologic failure is the point when a person's viral load rises significantly above the lowest level achieved during treatment. For example, a person who has achieved an undetectable viral load is failing treatment if his viral load rises above undetectable.

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When treatment is no longer effective, a person's viral load will increase while his or her CD4 T cell count decreases. To try to regain control of the virus, a new combination of medications must be used or adherence to therapy, if this is an issue, must improve. If left unchecked, drug resistance will build and the virus can take over the immune system, leaving a person unable to fight off infection and disease. When HIV progresses to this level, a person is more prone to opportunistic infections, which are illnesses that do not usually cause disease in people with healthy immune systems.

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There are a number of reasons why a treatment can fail. They include:

Suboptimal therapy - the virus is more powerful then the drugs prescribed to fight it. It continues to replicate and weaken the immune system, despite treatment.

Poor adherence - a person is unwilling or unable to take his or her medication exactly as prescribed.

Poor drug absorption - a person's body is not receiving the intended dose of the prescribed medication.

Drug resistance - mutations within the virus make it less susceptible to antiviral medications.

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Drug resistance means that the virus can adapt, grow and multiply in the presence of drugs designed to block it. HIV is considered to be resistant when a drug or class of drugs is no longer effective against it.

Though drug resistance commonly occurs in individuals on antiviral treatment, resistant strains of HIV can be transmitted from one person to another. Therefore, it is possible for someone newly diagnosed, and not yet on antiviral treatment, to be infected with virus that is resistant to one or more of the drugs used in HIV therapy.

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Each person's HIV is made up of different types, or strains of the virus. Drug resistance develops because HIV replicates (reproduces) very quickly and cannot correct mistakes made during the replication process. These mistakes, or mutations, cause some viral strains to become weaker, while other strains become stronger and less susceptible to antiviral drugs. The natural, most powerful, and most prevalent strain of the virus in a person's body that is susceptible to all antiviral drugs is referred to as the "wild-type" virus. The wild-type virus is the strain that physicians target with antiviral therapy.

While antiviral treatment slows the progression of the wild-type virus, strains that are less susceptible to treatment may continue to grow. If the virus develops resistance, the drug-resistant form multiplies, and becomes the dominant strain within the body, reducing the effectiveness of an individual's treatment.

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Antiviral medications are broken up into three classes: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Once a person's HIV has built up resistance to one drug in a particular class, it is possible for it to also be resistant to other drugs in the same class. This is called cross-resistance.

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Drug resistance occurs when viral mutations make certain strains within a person's body less susceptible to antiviral medications. Essentially, these mutations make the virus immune to a specific drug or class of drugs.

Current treatment guidelines recommend the use of two nucleoside reverse transcriptase inhibitors (NRTIs) plus one or two protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTIs). However, drug resistance can limit a person's treatment options, making it more difficult to achieve the recommended combination of medications. Without the appropriate combination, a person's virus can continue to multiply, further suppressing the immune system.

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The development of viral mutations that cause drug resistance cannot be completely stopped at this time; however there are certain precautions that a person can take to reduce the risk of developing drug resistance. The most effective measure is to adhere strictly to therapy. Another method of addressing drug resistance, referred to as sequencing, involves long-term treatment planning to manage treatment failure and drug resistance.

Adherence to medications
With the strict dosing schedule and challenging side effects that come with HIV therapy, many people have a hard time taking their medications properly. But proper adherence, or taking medications exactly as prescribed, is vital to the success of antiviral treatment. Partial adherence can lead to partial viral suppression, allowing resistant strains of the virus to grow faster.

Sequencing
Treatment sequencing is basically a long-term strategic approach to antiviral therapy. By utilizing information that is known about how resistance develops when certain drugs are used, healthcare providers can formulate combinations of drugs that will preserve more treatment options when therapy failure occurs later on down the road. This approach requires specific planning up-front as well as diligent maintenance, including strict adherence to treatment. Sequencing is ideally used in people who have not yet received antiviral therapy, but can be effective in treatment experienced people as well.

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