With the dizzying array of HIV meds now available and new drugs being added every year, it may seem difficult if not impossible to make sense of all the choices. But in reality, for someone starting meds for the first time, there are only a few combinations of drugs that are recommended, and understanding the options is not as hard as it seems.

In developed countries like the U.S., people with HIV have access to a range of first-line regimens and to second-line regimens if those fail. People in developing nations have fewer choices, although pills that combine certain drugs are available only outside the U.S. This article will cover all the drugs currently available, as well as the U.S. guidelines on which combinations are considered best. (For information on when to start treatment, see the "HIV Treatment Primer" in the Winter 2006 issue of ACRIA Update, available online at www.acria.org/treatment/primer.html)

What's Available?

Six different types, or classes, of HIV meds have received approval from the U.S. Food and Drug Administration (FDA). The best way to understand how these classes of drugs differ is to look at the life cycle of HIV and study how the drugs interfere with this process.

HIV is a virus, and viruses are very simple things. They are not even technically alive, since they are unable to reproduce on their own and consist only of a protein coat surrounding a simple piece of genetic material. The protein coat contains "spikes" that protrude and can attach to living cells. They're sort of like the burrs that you find in the woods sticking to your pants or socks. Viruses are very "sticky" since they must attach to a living cell in order to reproduce.

But each virus can attach to only a specific type of cell. Hepatitis viruses attach to liver cells, cold viruses attach to cells in the nose, and HIV attaches to any cell that has a CD4 receptor on its surface. This includes CD4 T cells, as well as other immune cells.

In order to reproduce, HIV must complete the following steps:

Click image to enlarge.

1. Grabbing onto the doorknob
   The process HIV uses to enter a cell can be thought of as opening a locked door. The first step is to grab onto the doorknob. HIV does this by grabbing onto the cell's CD4 receptor with one of the spikes on its surface. Drugs are being studied that may prevent this first step, but none have been approved yet. The immune system creates antibodies that fit over HIV's spikes in an attempt to prevent this step, but since HIV mutates (changes) so much, these antibodies are not able to stop all the HIV from attaching to CD4 cells.

2. Unlocking the door
   Once HIV has grabbed onto the doorknob (the CD4 receptor), the next step is to insert its key into the lock. It does this by linking up with one of two additional receptors, known as the R5 or X4 co-receptors. Almost all HIV infections are caused by virus that uses the R5 co-receptor. Virus that uses the X4 co-receptor usually appears later in the course of HIV disease.

   One drug has been approved that prevents HIV from attaching to the R5 co-receptor:

   Selzentry (MVC)

   It clogs up the co-receptor - kind of like putting glue into a lock to prevent someone from inserting a key. It was hoped that co-receptor inhibitors like Selzentry would be better than other types of HIV drugs, since they prevent HIV from even entering the cell. But Selzentry has so far been approved only as a second-line treatment, since early trials showed it didn't work as well as other meds in people who had never taken HIV drugs before. More studies are being done to see if it can be used as a first-line treatment, and other co-receptor inhibitors, like vicriviroc, are being studied in clinical trials.

   Selzentry works only against virus that uses the R5 co-receptor, so it is not used in people who have any X4 virus. The FDA recommends that people get a tropism test before starting treatment with a Selzentry. This blood test can tell if there is X4 virus in the body. If that's the case, Selzentry won't work.

3. Opening the door
   If HIV is able to attach to the CD4 receptor and to one of the co-receptors, it now attempts to "open the door" by fusing, or joining, with the cell's wall. It pulls itself right up against the cell wall and shoots a spike into the cell to open it.

   One drug has been approved to prevent fusion:

   Fuzeon (ENF)

   Fuzeon is also approved only as a second-line treatment, since it is a twice-daily injection and retails for almost $25,000 a year. In people who have become resistant to many HIV drugs, Fuzeon has been shown to be an important option to regain control of HIV. But it is usually used only if no other options are available.

4. Converting the RNA
   Unlike most viruses, HIV contains RNA, which is the mirror-image of DNA (the strand of proteins that carries every living cell's instructions). This is why HIV is known as a retrovirus, and why drugs that work against it are called antiretrovirals.

   Once HIV fuses with a CD4 cell, it inserts its RNA into the cell along with three enzymes it will use to reproduce. The first enzyme, reverse transcriptase, helps to convert HIV's RNA into DNA. There are two classes of drugs that interfere with this process.

   Nukes
   The earliest types of drugs approved to fight HIV were all nucleoside analogs, or "nukes" for short. Here's how they work: HIV creates new DNA using its RNA as a template - kind of like a printing press. It gathers nucleosides (simple proteins) from the cell and links them one by one into a DNA chain, using its RNA as the pattern. Nucleoside analogs are chemicals that are very similar to nucleosides, but they prevent the chain from continuing, since the next nucleoside cannot be attached to them.

   Many drugs fall into this class, and they form the backbone of many first-line regimens:

   Emtriva (FTC)
   Epivir (3TC)
   Retrovir (AZT)
   Videx (ddI)
   Viread (TDF)
   Zerit (d4T)
   Ziagen (ABC)

   (Videx and Zerit are not prescribed often, because of dosing and side effect concerns.)

   The nukes have also been combined into combination pills for easier dosing:

   Combivir (Epivir & Retrovir)
   Epzicom (Epivir & Ziagen)
   Truvada (Emtriva & Viread)
   Trizivir (Epivir, Retrovir & Ziagen)

   Since these drugs all interfere with the reverse transcriptase enzyme, they are also known as nucleoside reverse transcriptase inhibitors, or NRTIs.

   Non-Nukes
   Another class of drugs - the non-nucleoside reverse transcriptase inhibitors, (NNRTIs or "non-nukes") - also prevents HIV from completing its DNA chain. But this class interferes directly with the reverse transcriptase enzyme, which is needed to connect each nucleoside to the chain. They include:

   Intelence (ETV)
   Rescriptor (DLV)
   Sustiva (EFV)
   Viramune (NVP)

   Sustiva is often used as a first-line "anchor" drug of a three-drug regimen, since it has been shown to be very effective when combined with two nukes. Intelence was just recently approved, as a second-line treatment for people who are resistant to Sustiva and Viramune. (Rescriptor is rarely used because of dosing and effectiveness concerns.)

   One combo pill combines three of the most popular first-line drugs, and is taken just once a day:

   Atripla (Emtriva, Sustiva &Viread)

   Also, many combination pills containing generic HIV drugs are available only outside the U.S., including

   (AZT & NVP) (3TC, AZT & EFV)
   (3TC & d4T) (3TC, AZT & NVP)
   (3TC & TDF) (3TC, d4T & EFV)
   (TDF, FTC & EFV) (3TC, d4T & NVP)

5. Integrating the DNA
   Once HIV has converted its RNA into DNA (known as proviral DNA), its next step is to insert this DNA into the cell's DNA. It does this by entering the cell's nucleus (where the DNA is stored) and using another enzyme known as integrase.

   One drug that interferes with integrase has been approved:

   Isentress (RAL)

   Isentress is currently approved only as second-line treatment for those who are already resistant to other HIV drugs. Studies have shown it to be effective as a first-line treatment, but since it must be taken twice daily, it may not be as popular as once-daily regimens like Atripla.

6. Making more RNA
   Once HIV has inserted its DNA into a cell's DNA, it takes over that cell's functions. The CD4 cell is no longer an infection-fighting cell; it is now just a factory that makes more HIV. But there is another important fact for people with HIV: The virus usually must wait until the CD4 cell becomes "activated" before it can being making more HIV. And what activates a CD4 cell? An infection. So avoiding infections and treating infections quickly can prevent increases in the amount of HIV in the body. People with HIV should not let symptoms like fevers, diarrhea, or rashes, for example, go untreated for days. Calling a doctor quickly and starting treatment sooner rather than later can help to keep HIV levels low.

   If the CD4 cell is activated, the HIV DNA that has been inserted into the cell's DNA now instructs it to start making long strands of HIV RNA, enough for multiple copies of HIV. Each of these strands must be cut into exactly the right length for each new copy of HIV. To do this, the virus uses another enzyme known as protease.

   Protease was one of the first enzymes to be computer-imaged in three dimensions. Instead of just knowing which chemicals made up protease, scientists were able to see exactly how the enzyme was shaped. And they made an important discovery: Protease is shaped like a donut, with a hole in the middle. Using this hole, the enzyme moves along the RNA strand and snips off a piece of RNA exactly the right length for each new copy of HIV.

   Protease Inhibitors
   When they found out how protease worked, scientists were able to create the first "designer drugs" for HIV. Protease inhibitors are designed to fit directly into protease's donut hole, preventing it from cutting the RNA strands to the right length. While new HIV can still be produced, it is defective and unable to infect other cells.

   So far, nine protease inhibitors have been approved:

   Aptivus (TPV)
   Crixivan (IDV)
   Invirase (SQV)
   Kaletra (LPV/RTV)
   Lexiva (FPV)
   Norvir (RTV)
   Prezista (DRV)
   Reyataz (ATV)
   Viracept (NFV)

   Crixivan and Viracept are not used often because of dosing and side effects concerns, and Norvir is rarely used at full dose. But it is often used to boost the amount of other protease inhibitors in the body.

   Aptivus and Prezista are approved only as second-line treatments for those who are resistant to other HIV drugs.

7. Packaging and Budding
   Once HIV is able to package all the pieces it needs for new copies of HIV, it "buds" from the cell, taking a piece of the cell wall and snipping it off for its own coat. Each infected CD4 cell can make hundreds of copies of HIV before it dies from the infection.

   Drugs to prevent budding are currently being studied in clinical trials, but none are approved yet.

What to Start With?

This is the decision that almost everyone with HIV will have to make at some point, since over 99% of people with HIV will eventually need meds to control their virus. But since it may be years before a person needs to go on meds, it's smart to learn about the drugs before you need them and to decide, with your doctor, which drugs to start with.

There are U.S. guidelines, created by a panel of researchers, doctors, and consumers, on which drugs to start with. We know from long-term research that it usually takes at least three HIV meds to control HIV over the long haul. Using fewer than three usually allows HIV to mutate and become resistant to the drugs.

Current guidelines recommend starting with two nukes, along with either a non-nuke or a protease inhibitor. The preferred nuke combinations are Epzicom and Truvada. (Combivir is now listed as an alternate choice).

These should be taken with either a non-nuke or a protease inhibitor. The preferred non-nuke is Sustiva (Viramune is an alternate choice), and the preferred protease inhibitors are Lexiva, Kaletra or Reyataz (all taken with Norvir to boost their levels). (Invirase with Norvir is listed as an alternate choice.)

There is a variety of other combinations that are possible based on your particular situation. For example, people with kidney damage can't take Truvada, Viread, or Atripla. So, people with HIV need to work with their doctor to choose the first regimen that is best for them.

When to Switch

When used correctly, these combinations can lower the amount of HIV in the body by over 99%. This is confirmed by an HIV viral load test about a month after starting treatment. If the test shows that HIV levels have not dropped significantly by that time, it usually means that other drugs must be tried. The goal is to get HIV levels to below 50 copies per mm3 (cubic millimeter - a few drops of blood). This is known as an "undetectable" viral load; if this can be maintained, the drugs can work for many years.

If a regimen works at first, but then stops working, it is usually due to low levels of drug in the body. This is sometimes caused by not enough drug being absorbed into the body, but the most common cause is missed doses. Missing as few as three or four doses a month can cause HIV to mutate and become resistant to the meds. If a person has an undetectable viral load, but then sees it go up and stay up, that usually means resistance has occurred and it's time to switch to a new regimen.

What to Switch to

There is now a broad choice of drugs approved for people who are resistant to HIV meds, including Aptivus, Fuzeon, Intelence, Isentress, Prezista, and Selzentry. (Older drugs may also work if resistance has not developed to them.) A resistance test can provide good information on which drugs will no longer work for you, and will help your doctor choose a new regimen.

Many people have gone on to second and third-line regimens with success. The general recommendation is to switch as many drugs as possible, preferably all three. If only one drug is changed and HIV is resistant to the other two drugs, resistance to the new drug can occur within just a few months.

Staying Healthy in the Long Run

The best option is to make your first regimen work for you. Preparing to begin taking HIV meds means talking about ways to avoid missing doses, known as adherence. Many adherence counselors are available and have dozens of tips and tricks to help people with HIV take their meds correctly. Speaking with them before you start meds is the best way to achieve success.

Finally, staying healthy with HIV is not only about taking pills. Diet, exercise, rest, stress reduction, etc. all play important roles in supporting your immune system as it fights HIV. Using every tool at your disposal will not only delay the need for HIV meds, but help your body maintain health once you start them.

Mark Milano is an HIV Health Educator at ACRIA.