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How HIV Drugs Work 101

By Glen Pietrandoni, R.Ph.

September/October 2001

How HIV Drugs Work 101

Adapted from the 1998 edition of  HIV 101 Positively Aware by Enid Vázquez.

There are three categories of HIV antiviral drugs that have FDA approval. (Because HIV is a retrovirus, these drugs are also called antiretrovirals.) Nucleosides and non-nucleosides work to stop HIV from infecting cells and protease inhibitors stop infected cells, from reproducing the virus. In addition, new classes of drugs to treat HIV/AIDS are on the horizon. Fusion inhibitors, nucleotide inhibitors and immune modulators may be available in the near future.


Nucleoside reverse transcriptase inhibitors (NRTIs) are also known as nucleoside analogs, or nukes for short. As their name says, these drugs inhibit reverse transcriptase, which is an enzyme that HIV needs in order to infect cells. Retroviruses like HIV use reverse transcriptase to convert their RNA into DNA. Without the ability to create its DNA inside the nucleus (core) of a cell, HIV cannot infect that cell. (An enzyme is a cell protein that causes chemical reactions in other substances.) The HIV DNA then integrates with the DNA of certain cells in the body. DNA is the structure containing all of a person's genes.

Once proviral DNA has integrated into the body's natural DNA, HIV becomes a lifelong infection. (No virus has ever been cured with medicine. Some are naturally eliminated by Mother Nature, while others -- like HIV and herpes viruses -- are forever. Science continues to work on this.) Generally, HIV successfully converts into proviral DNA within 72 hours after infection. Once inside the cell's DNA, HIV awaits activation by cytokines and chemokines. In simple terms, these are chemical substances that tell cells what to do (thus, activating them).

NRTIs are analogs (think of the word "analogous," which means "similar") because they are imitations of the body's own nucleosides, which HIV uses to infect cells. The nukes trick HIV reverse transcriptase into using the worthless fake nucleosides, thus preventing the spread of infection to more cells. The virus thinks it is inserting a natural nucleoside into its DNA chain, but it's inserting the drug. This breaks the chain.

The HIV nucleoside analogs are not as potent as the other antivirals. The nukes interfere with other enzymes in the body that perform similarly to the HIV reverse transcriptase enzyme. As with the other drugs, serious side effects are rare, but need to be closely monitored. They can, rarely, be fatal. Retrovir (AZT) and Zerit (d4T, stavudine) cross the blood-brain barrier (see The Brain below).


Like the nukes, the non-nucleoside reverse transcriptase inhibitors (NNRTIs, or non-nukes) also keep HIV from infecting cells by interfering with the virus' reverse transcriptase. However, they do it in a different way. The non-nukes bind directly to reverse transcriptase, preventing further replication of the virus. The non-nukes are highly cross-resistant to one another. They are metabolized in the liver, so therapy needs to take special consideration of potential interactions with other drugs that are also processed hepatically (through the liver).

Rescriptor (delavirdine) is an inhibitor of the cytochrome P450 system (see below), while Viramune (nevirapine) and Sustiva (efavirenz) are inducers. Inducers increase drug metabolism, which in some cases results in lower levels of protease inhibitors. Thus the need for increased protease inhibitor doses. Sustiva has been placed in the strongly recommended category of the DHHS guidelines for treatment of drug-naive patients, along with most of the protease inhibitors, in combination with two nucleosides.

The non-nukes provide a choice for people who are intolerant of protease inhibitors, those who want to save the protease class for the future, or whose PI therapy failed them. Chances are, if you've never had a non-nuke, you would get beneficial results from adding one if you're on your third or fourth regimen. Some of the non-nukes might be considered a superior choice in that they are easier to take than the protease inhibitors. Viramune requires two tablets daily, with or without food. Sustiva requires three capsules once a day, also without food requirements. Soon, a single 600mg Sustiva tablet will be available to simplify regimens even further. The non-nukes also have fewer short-term side effects and are generally effective in crossing the blood-brain barrier (see Liver Metabolism below). Again, careful monitoring of severe reactions (such as rash) can prevent illness and even death.

Protease Inhibitors

Protease inhibitors, like the name says, inhibit protease. Almost every living cell has a form of protease, a digestive enzyme that breaks down protein. HIV protease is only one of several enzymes the virus uses to reproduce itself. The HIV protease works by cutting up long chains of the virus' proteins and enzymes into smaller pieces that go on to infect new cells. By blocking HIV protease -- or as some people say, by gumming up the HIV protease scissors -- these drugs keep the virus from making copies that can infect cells. Thus the drugs keep immature non-infectious virus particles from becoming mature infectious particles. HIV protease works near the end of the replication cycle of the virus. As shown by the way in which antiviral drugs work, the HIV protease inhibitors can slow virus production in both newly infected cells and cells that have been infected for a long time, compared to the nukes and non-nukes which do not work on longtime infected cells.

The protease inhibitors are for the most part very powerful in relation to the nucleosides and have received major public attention. The protease inhibitors also do not generally have overlapping toxicities with the other two classes. However, they may be difficult to tolerate because of side effects like gastrointestinal symptoms. As with the nukes and non-nukes, some long-term side effects are still not understood. Researchers are working to understand the obvious relationship between protease inhibitors and very serious long-term side effects such as hypercholesterolemia and fat redistribution. Other abnormalities include the development of heart disease and diabetes in people who are predisposed to these conditions. The nukes and non-nukes are also potentially involved in the development of these problems.

As with the non-nukes, there is a lot of cross-resistance among the protease inhibitors despite different patterns of drug resistance among them. For this reason many specialists once believed that people with HIV may have only one shot at taking a protease inhibitor. With the introduction of Kaletra (lopinavir/ritonavir) and the increased usage of dual protease combinations, this may no longer be true. The protease inhibitors also have poor penetration into the cerebral spinal fluid (CSF), although again, the clinical benefits of this are unclear. Crixivan (indinavir) has the highest penetration of CSF of all the protease inhibitors. The PIs are highly protein bound. This means they are attached to proteins in the bloodstream. It is unbound drug that is active (gets absorbed), so the higher the protein binding the less drug is available to work. This creates a bioavailability problem. Protein binding, bioavailability, and metabolism in the liver (which can cause drug interactions with other drugs metabolized in the liver) all can lower the concentration of protease inhibitors in the body. However, most people achieve adequate drug levels at the doses prescribed. Some clinics are now using Therapeutic Drug Monitoring (TDM) to measure how much drug is available in your blood. At some time in the future, we may be ready to prescribe "Designer Drugs" and customize doses of drugs for each individual.

A Note About Adherence

A discussion of "How Drugs Work" must include a mention about adherence. Because the amount of drug needed to suppress the virus must be above a certain level at all times, missing doses will allow the virus to fight back and reduce the effectiveness of the drug therapy. Think of the drugs as a dam holding back a river (the virus). If the dam is not tall enough (not enough drug), the water will just pour right over the wall (viral replication). Food is also important in making sure there is enough drug to fight the virus. Most protease inhibitors (except Crixivan) must be taken with food to be absorbed into the blood. Other drugs like Videx and Crixivan require an empty stomach because stomach acid destroys the medication before it is absorbed into the bloodstream. [See "Adherence 101" and "To Start or Not Start?"]

Some HIV drugs will require closer monitoring, and sometimes dose reductions, to decrease the risk of side effects or toxic levels of drugs in the blood. Other HIV drugs can have the opposite effect, and may require increase in dosage in order to achieve adequate blood levels. Liver disease such as hepatitis, inherited deficiencies in the CYP genes, and multiple medications can cause problems with drug metabolism. Doctors use information on how drugs affect the different CYP450 enzymes (there are more than three hundred of them) to help determine which drugs to use in combination therapy and the doses to be used.

See Positively Aware 2001 Drug Guide for a complete listing of currently available HIV antivirals.

Quick Tips

Doctors are often difficult to get a hold of. A pharmacist who is knowledgeable in HIV/AIDS can help you take your medications correctly. Take a list of current medications with you to the doctor's office and to the pharmacy. This helps avoid potential drug interactions when getting new meds. Also tell the pharmacist about over-the-counter medications that you take, vitamins and herbal supplements, and drugs you may receive from other pharmacies. Those folded-up, tiny-lettered package inserts that come with medications explain many issues affecting therapy, such as how that particular drug works, its known interactions with other drugs, and results from clinical trials. Save those inserts for future reference (such as when serious side effects start to hit). Know the names of your drugs and the correct doses. This will help you understand the doctor and pharmacist when discussing your treatment.

The Brain

While not proven, it is hoped that medications which cross the blood-brain barrier will help prevent or even treat neurological disorders such as ADC (AIDS Dementia Complex). AZT has been shown to prevent and treat dementia, while Ziagen, Sustiva, Epivir, Viramune, Zerit and Crixivan may also help. The body protects the brain -- its command center -- by making it difficult for various chemicals to enter this barrier. To date, the usefulness of using an antiviral drug that can enter the central nervous system (composed of the brain and the spinal cord) is based more on clinical experience than proven fact. Drug therapy from all three classes of drugs have been found to decrease neurocognitive impairment and has even increased survival for people with serious neural disorders.

Liver Metabolism

The cytochrome P450 (CYP) system, a family of enzymes, breaks down drugs in the liver. All of the non-nukes and the protease inhibitors go through these enzymes. Some of them are inhibitors of P450 enzymes. Inhibitors impair the liver's ability to break down other drugs. As a result, the blood levels of these other drugs may increase (with increased toxicities and side effects).

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