SEPTEMBER 1998

NUMBER ONE

Drug Resistance
Mutations lead to drug failure.

Drug resistance is another factor that causes HIV drug failures. This occurs when HIV mutates or changes its genetic structure. Missing doses can lead to drug resistance, which has led experts to sound the alarm about the need for strict adherence to drug schedules. As anyone taking HIV drugs knows, that's very hard; many people regularly skip doses because they forget or because the regimens are simply too demanding.

But skipping doses is only one explanation for drug failure. Due to the high genetic variability of HIV, drug-resistant strains may be present even in the absence of therapy, researchers say. That's because HIV shuffles its genes once every time it copies itself-some 10 billion times a day. As the virus mutates, different strains evolve. Thus, with every round of HIV replication, there's an increased risk of HIV resistance.

Drug studies show that a single mutation by HIV can make it resistant to a given drug, as is the case with 3TC and Viracept (nelfinavir). That's why monotherapy-use of a single drug-is not recommended. HIV resistance to one drug also leads to cross-resistance with other drugs in the same class; if you're resistant to AZT, you may be resistant to 3TC, for example. But the opposite also occurs: HIV mutations can also make the virus newly vulnerable to drugs it had previously overcome. That is why it's so important to choose your initial and follow-up regimens very carefully-to avoid multiple drug-resistant strains from emerging.

The best way to do this is to keep your viral load as low as possible. Experts also advocate early treatment to prevent HIV from naturally mutating into drug-resistant strains. They also suggest switching drugs relatively early when a regimen shows signs of failing.

The reasons for drug failure are complex and vary from person to person. At the top of the list is the potency of your drugs: Although current three-drug combinations can push HIV down to below detectable levels in many individuals, that doesn't spell zero activity. Instead, HIV may still be actively reproducing but at a level that can't be picked up by current viral-load tests. The drugs may also take longer to reach tissue compartments like the brain than the blood or lymph nodes.

Dosing and Drug Absorption: Metabolism is the way the body detoxifies drugs, breaking some down in the liver so they can more easily circulate or be excreted. Every individual has a different rate of metabolism, and factors such as body weight, absorption, distribution of the drug, and rate of excretion may affect drug levels in the blood. HIV itself and HIV drugs can lower stomach acid, while infections such as diarrhrea affect drug absorption.

Taking a drug on schedule at the recommended dose keeps the drug at an effective concentration in the blood. The trough level of a drug is its lowest level in the blood. Since each d.e.s. drug has a specific half-life-how long it takes to reach a peak concentration-it becomes a very difficult for doctors to measure how well a complex drug regimen is being absorbed in an individual patient.

Drug interactions can also occur when different HIV drugs are taken together. These can decrease or increase the concentration in the blood of a given drug. Other drugs, as well as supplements or steroids that are processed by the liver, can also interact with HIV drugs. That complicates the issue of drug interactions, which may lead to side effects.

P450 Liver Pathways: Many HIV drugs are processed by the same liver enzymes in the body, a metabolic pathway called cytochrome p450. There are more than 25 human p450 enzymes (also called isoforms) grouped into four families and six major sub-families; each is classified using Roman numerals and letters. About half of human drugs are metabolized by p450 3A4; another 30 percent use p450 2D6.

When you swallow a drug, it goes from your stomach into your intestinal tract, then into the liver. Imagine your liver as a processing factory with several p450 doorways: If two drugs use the same p450 enzyme, one has to wait while the other is getting broken down. That is called inhibition. A p450 inhibitor is any drug that inhibits the metabolism of another drug by an enzyme in the p450 family. Inhibitors usually increase concentrations of other drugs. Once a p450 inhibitor is cleared from the system, the inhibition stops. In other cases, one drug will decrease the metabolism of another drug: It is a p450 inducer (see "p450 Metabolism").

The protease inhibitor ritonavir, for example, is a p450 inhibitor that increases the blood level of another drug, rifabutin, by nearly fourfold. Some HIV drugs get broken down by more than one p450 enzyme, making them p450 inhibitors and inducers. Unfortunately, it's almost impossible for even the experts to predict how a given combination of HIV drugs will work together. This is particularly true for people whose old regimens are failing.

Measuring Drug Resistance TWO TYPES OF DIAGNOSTIC TESTS EXIST TO DETERMINE IF A PERSON has developed a drug-resistant strain of HIV: phenotypic and genotypic tests. Resistance occurs when the virus changes its genes, something called a point mutation. A phenotypic test shows, in a laboratory culture, how well HIV grows in the presence of a given drug. A genotypic test looks at the genetic code of an individual's HIV strains and can reveal a pattern of drug resistance. Genotypic tests include Specialty Laboratories HIV-1 GenotypeR Plus, LabCorp/Roche's HIV-1 Gene Chip, Virco's VircoGen, and Glaxo-Wellcome's LIPA-HIV-RT. Virco has a phenotypic test called Antivirogram. There's also Murex's rapid-resistance test. Most are expensive. Consult your doctor.