There are currently five categories of HIV antiviral drugs available that have FDA (U.S. Food and Drug Administration) approval. These categories are:

• nucleoside reverse transcriptase inhibitors (NRTIs)

• nucleotide reverse transcriptase inhibitors (NtRTIs)

• non-nucleoside reverse transcriptase inhibitors (NNRTIs)

• protease inhibitors (PIs)

• fusion inhibitors

Fusion inhibitors work outside the CD4 cell by inhibiting HIV from joining, or fusing, with the cell. Nucleosides, nucleotides and non-nucleosides all work to stop HIV from infecting CD4 cells. Protease inhibitors stop infected cells from reproducing the virus.

NRTIs

Nucleoside reverse transcriptase inhibitors, commonly referred to as NRTIs or nukes for short, inhibit reverse transcriptase, an enzyme that HIV needs in order to infect CD4 cells. Retroviruses, such as HIV, use the enzyme reverse transcriptase to convert their RNA into DNA, the structure that contains all of a person's genes. Without the ability to create the DNA inside the nucleus of a healthy cell, HIV cannot infect that cell. The HIV DNA then integrates with the DNA of cells (the CD4 cells, also called T-cells) in the body. A category of drugs called "integrase inhibitors" are in development to work at this stage of the virus.

Once proviral DNA has been integrated into the body's natural DNA, HIV becomes a lifelong infection. HIV drugs provide the body with a strong defense against the reproduction of HIV; however, they do not kill the virus. Generally HIV converts into proviral DNA within 72 hours after infection. Once inside the cell's DNA, HIV awaits activation by cytokines and chemokines, chemical substances that tell cells what to do.

NRTIs are analogs because they are imitations of the body's own nucleosides, which HIV uses to infect cells. Hence, you will hear the term "nucleoside analogs" used to refer to NRTIs. The NRTIs trick the HIV reverse transcriptase into using these imitation nucleosides, incorporating the imitation nucleoside into the HIV DNA chain. The virus thinks it's inserting the cell's nucleoside into its DNA chain, but it's actually inserting the drug. This breaks the viral DNA chain.

Drugs in the NRTI category include Retrovir (AZT), Zerit (d4T), Hivid (ddC), Epivir (3TC or lamivudine), Videx (ddI), Ziagen (abacavir) and Emtriva (FTC or emtricitabine). Combinations of these drugs are also available, such as Combivir (Retrovir and Epivir together in one pill) and Trizivir (Retrovir, Epivir and Ziagen). Epzicom, which was just approved by the FDA, is a once-daily combination of Epivir and Ziagen. Side effects to beware of with NRTIs include pancreatitis, rash, flu-like symptoms and peripheral neuropathy (a type of nerve damage).

Nucleotides

Viread (tenofovir) is the first drug (and so far, the only one) in the category of nucleotide reverse transcriptase inhibitors (NtRTIs) to be approved by the FDA. NtRTIs are very similar to the NRTIs, but are chemically pre-activated, to quickly convert to the actual form of drug in the body, allowing the NtRTIs to enter the HIV's DNA more rapidly than the drugs in the NRTI class. Viread and the NRTI Emtriva are now available in a combination once-daily tablet called Truvada.

NNRTIs

Like the NRTIs, 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 this in a slightly different way. The NNRTIs attach themselves directly to reverse transcriptase so that the RNA cannot make DNA, thus preventing further replication of the virus. The downside to this class of drugs is that NNRTIs are highly cross-resistant to one another (see "Resistance to HIV Medications" below).

The NNRTIs provide a choice for people who are intolerant of protease inhibitor side effects, those who want to save the protease class for future use, or for those whose protease inhibitor therapy failed them. Drugs in the NNRTI class include Rescriptor (delavirdine), Viramune (nevirapine) and Sustiva (efavirenz). Sustiva has been placed in the "preferred" category in the current federal guidelines for those starting HIV treatment. Viramune and Sustiva are also both easy to take. Viramune requires two tablets daily (one twice a day) while Sustiva requires just one tablet daily, usually taken at bedtime.

Rash is a side effect that all NNRTIs share in common, and is one of the more prevalent side effects in the class. Other common side effects, usually associated with Sustiva, include confusion, abnormal thoughts, vivid dreams and impaired concentration. These side effects, though, usually disappear after two to four weeks of therapy.

Protease Inhibitors

Protease inhibitors (commonly called PIs), inhibit protease, a digestive enzyme that breaks down protein. HIV protease is only one of several enzymes that the virus uses to reproduce itself. The HIV protease works by cutting up long chains of the virus' proteins into smaller pieces that go on to infect new cells. By blocking HIV protease, these drugs keep the virus from making copies that can infect cells. Thus, these drugs keep immature non-infectious virus particles from becoming mature infectious particles, which cannot infect any other cells.

There are currently nine PIs on the market, making it the largest category of HIV drugs available. Protease inhibitors are generally thought to be the most potent or the "heavy-weights" of the HIV drugs, and Kaletra is considered, so far, to be the undisputed champion of the heavy weights. Kaletra is the other drug, along with Sustiva, to be placed in the "preferred" category in the current federal guidelines for HIV treatment. It has proven to be a very durable drug and has become the most-prescribed drug in the protease inhibitor class.

Other PIs in the class include: Agenerase (amprenavir), Invirase (saquinavir hard-gel), Fortovase (saquinavir soft-gel), Crixivan (indinavir), Norvir (ritonavir), Viracept (nelfinavir), Lexiva (fos-amprenavir) and Reyataz (atazanavir). Lexiva and Reyataz, the two newest PIs, can be dosed just once daily and both are usually boosted with Norvir, an older PI, which raises the levels of the drugs in the body. Norvir is also contained in Kaletra and is used to boost the other ingredient of the drug, lopinavir. Norvir is also used to boost Crixivan and Fortovase. Another PI, Viracept, is now available as a 625 mg tablet. This reduces the dose to only two 625 mg tablets twice a day, as compared to the original dose of five 250 mg tablets twice a day.

Though the protease inhibitors are considered to be the most potent of the HIV drugs, they are not without problems. PIs can cause blood glucose levels to rise in people with diabetes and can even bring on new cases of the disease. PIs can also increase the levels of cholesterol and triglycerides in the blood, putting you at risk for a heart attack. Other side effects include: kidney stones with Crixivan, diarrhea with Viracept, hyperbilirubinemia with Reyataz, and all of them can cause nausea and diarrhea.

Tipranavir will likely be the next PI to be approved by the FDA. It is in the latter phase of clinical trials and will be the first non-petidic protease inhibitor (NPPI) available to treat HIV infection. A new 500 mg tablet of an older PI, Invirase, is also expected to be approved this year.

Fusion Inhibitors

While the NRTIs, NtRTIs, NNRTIs and PIs are all working inside the infected CD4 cell to treat HIV, fusion inhibitors fight HIV outside the CD4 cell by blocking fusion of HIV before the virus enters the cell and begins its replication process. Fuzeon is the first (and thus far the only) in this class of drugs to be FDA approved. Administration by twice daily subcutaneous injection and its high cost have limited the use of this drug. The most common side effect of Fuzeon, due to its route of administration, is injection site reactions. To help avoid this side effect, rotation of injection sites is recommended.

Adherence to HIV Medications

What exactly is adherence when talking about HIV medications? Simply put, adherence is sticking to your program -- taking the medications you're supposed to take, on time, every time! Whether you've been on HIV medications for 10 years or are just starting out, it takes a strong personal commitment to take your medications on time, every time. Non-adherence is the number one reason why HIV treatments fail. These medications work -- but they can't work if you're not taking them! So, here are some tips and suggestions to help you achieve adherence with your HIV medications.

1. Make sure you're mentally ready to start taking HIV medications.
   Not sticking to your regimen makes it very easy for the virus to mutate and develop resistance to the medications, and then you may have wasted the regimen. Don't start taking the medications until you are totally committed to taking them right on time, every time!

2. Keep your medication regimen simple.
   Nowadays, simplifying your HIV regimen is often easily done, thanks in part to combination drugs such as Trizivir, Truvada, Combivir and Epzicom. These drugs combine two or three drugs into one tablet, which reduces pill burden and makes dosing simpler. In fact, Truvada and Epzicom are only taken once daily. Newer protease inhibitors such as Lexiva and Reyataz can also be taken just once daily. Plus, some older drugs such as Sustiva and Viracept are available in higher strengths, also reducing pill burden. Sustiva is also another drug that only has to be taken once daily. Talk with your physician about keeping your regimen simple and easy. Reducing the pill burden and using once daily regimens can greatly increase medication adherence.

3. Use reminders.
   Some people use timers or pagers set to go off when it's time to take medications to help them remember to take their meds. Other people take an activity they do every day and link that activity to taking their medications, such as before, with or after meals, before or after showering or brushing teeth or first thing in the morning or right before bedtime. A basic seven-day pillbox is also one of the most useful tools to help with adherence. The pillbox can be stacked with meds once a week with the meds being put in the correct day and time slot. Many pillboxes also are made so that each day can be popped out of the holder and taken with you.

4. Get help from family and friends.
   Family and friends can help you stick to your regimen, so don't be afraid to rely on them. Let them know exactly what you're supposed to take and when. You can also ask them to help you remember to take your drugs, which can be easily done with just a simple phone call!

Resistance to HIV Medications

If the anti-HIV drugs are not kept at a steady level in your body, HIV can quickly make copies of itself and that leads to resistance. Resistance is when HIV is able to resist the effects of the anti-HIV drugs in your body. When that happens, the drugs will not work as well -- or even not at all -- in stopping HIV from spreading throughout your body. If HIV becomes resistant to a medication, the virus can sometimes become resistant to other medications in the same drug class. This is called "cross-resistance." When this happens, you lose the chance to use another drug from that class, or several of them and possibly even all of them. The NNRTI class drugs are highly cross resistant to one another. Some PIs are also cross resistant to one another.

With new drugs such as tipranavir and SCH-D in development, people who are already resistant to other anti-HIV drugs will get another opportunity to continue drug therapy in the battle against HIV.

Steve Meyer is a registered pharmacist with Pharmacare Pharmacy, located at 3337 N. Broadway in Chicago. Steve also assisted with Positively Aware's first two annual HIV Drug Guides, in 1997 and 1998.

To read Part One of this series, click here.