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.
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).
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.
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.
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 TipsDoctors 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.