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Antiretroviral drugs are used to treat the human immunodeficiency virus (HIV). Patients take antiretrovirals in "combination therapy," which typically involves a 3- or 4-drug combination of nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. In the right combination, and when taken according to schedule, antiretrovirals can slow down the development of AIDS.

Antiretroviral therapy helps people who are infected with HIV to live longer, healthier lives. Although AIDS remains an epidemic in many parts of the world, the death rate from the disease has fallen drastically in the United States and other industrialized nations where people have access to affordable antiretroviral drugs.

Antiretrovirals, when taken in the right combination and according to schedule, can result in immune reconstitution, restore health, and prevent the development of AIDS and AIDS related conditions. As of January 2008, there are 32 antiretrovirals approved by the U.S. Food and Drug Administration (FDA).

Challenges of Antiretroviral Therapy

Despite the effects that antiretrovirals have on AIDS, they do not cure the disease. Most people remain infected for life, no matter how effectively antiretroviral drugs keep the viral load down and boost the immune system.

Antiretrovirals do not prevent HIV transmission. In spite of potent antiretroviral combinations, people who are infected with HIV can still transmit the virus. They must practice safer sex and refrain from certain behaviors to avoid infecting others.

Several antiretrovirals must be taken together to be effective. Using antiretrovirals in various combinations delays resistance and enhances the potency of the drugs. Resistance, which can take weeks to months to evolve, occurs when a mutation in the structure of the virus enables it to evade the action of the drugs. Once HIV becomes resistant to a drug, the drug is no longer effective.

Patients who take antiretrovirals should be aware that long-term effects of taking the drugs every day for many years are not yet known. Long-term health complications may include many problems, such as premature cardiovascular disease.

Antiretroviral therapy poses a complicated challenge to patients and health care practitioners for the following reasons:

• Patients must adhere to a strict regimen, which usually means they must organize their lives around taking the drugs.
• Treatment requires an individualized combination of drugs.
• Therapy requires life-long monitoring of HIV resistance and drug efficacy.
• HIV can still develop resistance.
• Drug-drug interactions can have severe, sometimes deadly, adverse consequences.

Physicians and patients must weigh potential costs and benefits of antiretroviral therapy, as well as the risk for disease progression (i.e., the risk for developing AIDS or AIDS related complications). Decisions regarding if and when to start therapy, which drugs to choose, and when to change drugs are based on each patient's individual circumstances and on detailed knowledge of the patient's medication history.

Starting Antiretroviral Therapy

Because the human immunodeficiency virus will likely evolve resistance if combination therapy is started but not adhered to, it is essential for patients who choose antiretroviral therapy to understand the consequences of missing doses. Patients must make a life-long commitment to the therapy. Carelessness increases the development of HIV resistance and may increase the risk for spreading infection with resistant HIV.

Should antiretroviral treatment be started during the primary HIV infection? Primary infection, or acute HIV syndrome, is the period between initial infection and the development of antibodies to HIV. It occurs approximately 3 to 6 weeks after infection. The clinical benefits of potent antiretroviral therapy at this early stage of HIV infection are unknown. Some physicians and researchers believe that early intervention is best, but potential long-term toxicity and other side effects must be carefully considered. Patients should discuss potential advantages and disadvantages of starting antiretroviral therapy early in the course of infection with a qualified health care provider.

ARVT types

As of January 2008, there are 32 FDA-approved antiretrovirals in use in the United States. Types of antiretrovirals include the following:

• Nucleoside reverse transcriptase inhibitors (NRTIs)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Protease inhibitors (PIs)
• Fusion inhibitor (e.g., enfuvirtide [Fuzeon®])
• Entry inhibitor (e.g., maraviroc [Selzentry®])
• Multi-class combination drug (e.g., Atripla®)
• HIV integrase strand transfer inhibitor (e.g., raltegravir [Isentress®])

More information about antiretrovirals and other HIV/AIDS drugs can be found at the U.S. Department of Health and Human Service AIDSinfo Drug Database, which contains information about pharmacology (how a drug works in the body), usage, side effects, and contraindications (a symptom or circumstance indicating that the patient should not take a drug).

Antiretroviral medications can cause a redistribution or accumulation of body fat and can raise cholesterol and other fat levels in the blood. The cause and long-term consequences of these effects are not well understood.

Drug failure

Drug failure is the failure of a drug to continue to do the job it is supposed to do. With regards to HIV/AIDS, the American Medical Association defines drug failure as the following:

• Inadequate viral suppression (inability to keep HIV RNA at an "undetected" level)
• Unsatisfactory increase in CD4+ count
• Progression of clinical symptoms due to immune dysfunction

Most practitioners focus on the first of these 3 criteria—the change in viral load. In many cases, the decision to change therapy is somewhat subjective. Most practitioners do not recommend changing therapy solely on the basis of the CD4+ count, since the relationship between a change in CD4+ and drug effectiveness is not clear.

It is important to make an effort to determine what has caused the drug failure. The primary cause of drug failure is lack of adherence, which leads to resistance. If drug failure is due to dose adherence problems, what can be done to help the patient follow the regimen more carefully? Is drug failure due to adverse drug interactions or other pharmacological problems? Is it due to resistance that has evolved despite that fact that the patient has faithfully adhered to the dosing schedule? These are important questions to ask.

Drug choice

It is extremely important that patients know as much as possible about certain combinations of drugs before agreeing to take them. To prevent resistance and drug failure due to missed doses, patients must be sure that they can comply with the dosing schedule their individualized combination requires.

Physicians choose drugs for the patient based on the most current available drug information and a detailed patient medical history. There is no evidence to suggest that any one combination of drugs is better than another and decisions usually are based on the patient's circumstances. Each drug regimen has advantages and disadvantages. Generally, an initial regimen of 2 nucleoside reverse transcriptase inhibitors (NRTIs) coupled with 1 or 2 protease inhibitors, or 2 NRTIs and a non-nucleoside reverse transcriptase inhibitor (NNRTI) is recommended. Other combinations are being studied, especially more potent combinations for patients with CD4+ count below 50 x 106/L or HIV RNA greater than 100,000 copies/mL.

Importance of Following the Dosing Schedule

Antiretroviral combination therapy requires taking more than 20 pills every day, at certain times, and expressly with or without food. Keeping to the schedule is a chore and challenge for many patients.

Why is it so important to stick to the schedule? Studies have shown that noncompliance can lead to the development of resistant HIV, drug failure, and the progression of disease. Studies also have shown that adherence increases the effectiveness of the drugs. Patients need primary care physicians and other sources of support who are committed to helping them stick to the regimen.

Resistance

HIV reproduces very quickly in the human body and is prone to developing genetic mutations (changes in its genetic makeup). These mutations allow the virus to adapt to new environments. Rapid reproduction and the tendency to change and adapt mean that the virus can develop resistance to medications, if they are not taken properly. When a virus becomes resistant to a medication, that medication can no longer kill the virus.

At least three antiretroviral medications must be taken in proper doses and at the proper times to prevent HIV from reproducing and developing resistance. Once the virus becomes resistant to certain medications, those medications may never work again.

Several studies have proven that 100% compliance with the patient's antiretroviral therapy is essential to achieve maximum viral suppression. Even a rarely missed dose can dramatically affect the level of suppression, as illustrated with the following examples:

• 90% compliance may have only a 65% chance of suppressing the virus.
• 80% compliance may have only a 50% chance of suppressing the virus.

Because keeping the virus load down to an undetectable level in the blood is the goal of antiretroviral therapy, 100% compliance is essential.

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