Scientific American, 7/98, Douglas D. Richman, page 68
How Drug Resistance Arises
When anti-HIV therapy fails to keep HIV levels suppressed, the cause is often viral
resistance to at least one of the drugs being administered. How does such insensitivity
develop? At its root, resistance is mediated by mutations in viral genes. The genome
(complete set of genes) in any HIV particle serves as the blueprint for enzymes and other
proteins needed to make new copies of the virus. Current anti-HIV drugs, or
antiretrovirals, bind to specific HIV enzymes and impede their activity. Gene mutations
can alter these enzymes in ways that diminish this binding or otherwise undermine the
pharmaceutical attack. Some medicines, including the nonnucleoside reverse transcriptase
inhibitors, can be undone by a single mutation; others, such as the protease inhibitors,
require multiple mutations in a single genome.
Ironically, use of an antiretroviral can actually promote proliferation of drug-resistant HIV variants. The reason relates to HIV's rapid and relatively sloppy replication. Unchecked, HIV makes roughly 10 billion new viral particles every day in an infected individual. Yet it does so without great attention to accuracy. Hence, the genome of each new particle is likely to differ from the "parent" genome in at least one spot. Coupled with HIV's prolific rate of reproduction, this inaccuracy means that every mutation able to cause or contribute to drug resistance is likely to be generated daily in one or another HIV particle. In other words, even if a patient has never been treated, any compound that is delivered will encounter some HIV variant that is already resistant or is on its way to accumulating the full set of mutations needed for resistance.
Now consider what happens when a patient takes an antiretroviral. For argument's sake, let's say this medicine can be thwarted only by five mutations in a genome. The drug will bar reproduction by variants that are still sensitive to the agent, but HIV subpopulations that are somewhat insensitive will continue to proliferate to an extent. (In advance of therapy, most variants probably will carry no more than two resistance mutations.) Over time, the ongoing replication will enable at least some of the semiresistant variants to acquire another resistance mutation. If the drug is still present, these forms of HIV will outpace
their more susceptible cousins and will have the opportunity to acquire the other needed genetic alterations. At that point, they will evade the antiretroviral entirely and grow unchecked.
n other words, use of an anti-HIV agent will "select for" the T development and growth of resistant strains unless the agent blocks all viral proliferation. Similarly, if resistant virus is present when a drug is first delivered, the compound will permit growth of the resistant population and will fail quickly.
Because resistance can occur readily, and because no single pharmaceutical on the market is powerful enough to suppress HIV on its own, physicians no longer treat patients with single drugs (monotherapy). They often choose combinations that both maximize potency and reduce the likelihood of resistance. For example, physicians try to avoid anti-HIV drugs the patient has taken before, under the assumption that past use will have helped establish insensitive HIV populations.
Having selected a therapy, doctors must also stay on the lookout for signs of emerging resistance. In general, if virus is detectable in the blood after four to six months of therapy-whether because of inadequate drug potency, insufficient drug absorption or poor adherence to the drug regimen-its presence warns that replication is occurring and that resistance has developed or is likely to follow.
Tests still under development may improve the ability to tailor therapies to individual patients. One kind will examine the genetic makeup of the HIV variants in individuals, to determine which resistance mutations they carry. The other will assess the extent of resistance to particular drugs. With such information, physicians will be able to select antiretrovirals that are least likely to meet resistance. Also, if viral levels in a patient begin to rise, the tests should reveal whether resistance is at fault and should help physicians to identify alternative therapies having the best chance of success.