Common Sense About AIDS

Drug-resistance tests detect the mutations of HIV

Enzymes are the key

Although scientists and investigators have created many drugs to combat HIV, the virus often mutates and finds ways to thwart some of these drugs’ efforts. So a new and increasingly important aspect of HIV antiretroviral treatment is drug-resistance testing.

ViroLogic, Inc. of San Francisco has prepared a booklet that answers questions about HIV drug-resistance testing. The booklet, titled "A No-Nonsense Guide to HIV Drug Resistance Testing," was written by Tim Horn, executive editor of The PRN Notebook, published by the Physicians’ Research Network in New York City, and Spencer Cox, an advocate for people with HIV/AIDS. The following questions and answers are excerpted from the booklet:

What is drug resistance?

HIV drug resistance refers to a reduction in the ability of a particular drug or combination of drugs to block reproduction or "replication" of HIV. For people infected with the virus, drug resistance can render drugs less effective or even completely ineffective, thus significantly reducing treatment options.

Resistance typically occurs as a result of changes — called mutations — in HIV’s genetic material, which is called RNA. Mutations of RNA lead to changes in certain proteins called enzymes. These enzymes control the production of HIV. Mutations are especially common in HIV, because this virus reproduces extremely quickly and does not contain the proteins needed to correct mistakes made during copying of the genetic material. HIV relies on many enzymes — such as reverse transcriptase, integrase, and protease — to replicate inside a human cell. If a mutation in the reverse transcriptase gene occurs, that change will remain in the virus for as long as it replicates or until another copying error alters its form yet again. Some mutations cause the virus to become so weak that it cannot replicate effectively; other mutations cause the virus to become even more virulent.

What’s with all the strange numbers?

A lot of medical information available to both health care providers and people living with HIV frequently discusses specific mutations. One example is the classic 3TC mutation: M184V. The 184 refers to the amino acid position on the reverse transcriptase enzyme. The M — which stands for methionine — is the amino acid at position 184 of a wild-type (drug-sensitive) virus’ reverse transcriptase enzyme. The V — which stands for valine — refers to the mutation that results in drug resistance. In other words, the amino acid methionine at position 184 has been replaced by a valine. This change thus prevents an antiretroviral drug from binding with the enzyme to prevent the virus from replicating.

How can drug resistance be measured?

Over the past five years, a significant number of breakthroughs have been made in understanding the power of antiretroviral drugs against HIV. With the development and availability of viral-load tests — such as PCR, bDNA, and NASBA — we can determine from a blood sample how much virus is replicating in the body. If viral load increases substantially while a person is on a combination of antiretroviral drugs, the most likely culprit is drug resistance. Unfortunately, viral-load tests cannot determine whether or not HIV is resistant to one drug in particular or the entire combination. Moreover, in a person with drug-resistant HIV, these tests cannot determine which drug or combination of drugs is likely to be the most effective in the future.

Two general approaches are now used for measuring resistance to HIV drugs. The first is called genotypic testing. Genotypic tests can help determine whether specific genetic mutations are causing drug resistance and drug failure. The second method, called phenotypic resistance testing, is a more direct measure of resistance, and, more specifically, of the sensitivity of a person’s HIV to particular antiretroviral drugs.

How can these tests help decide on an initial treatment regimen?

Based on what is known about HIV’s error-prone replication process, we can assume that all patients have at least a few subpopulations of HIV that are resistant to individual drugs. However, these strains are often too limited in number and strength to compete with wild-type virus, and they stand a good chance of being killed off by initiating combination antiretroviral therapy. After all, the purpose of combination therapy is to serve as a multipronged attack on such strains.

A potential threat, however, is the transmission of multidrug-resistant strains of HIV. Multidrug-resistant HIV is defined as a strain of the virus that has limited or no sensitivity to several antiretroviral drugs. Such viruses usually emerge in HIV-infected people who were not prescribed drugs in the optimal way or who were not able to adhere to the challenging demands of drug-taking schedules. People harboring such virus can then transmit it to others.

Some researchers have found that HIV is either partially or fully resistant to one or more of the commonly used antiretrovirals for 10% to 30% of newly infected people. Such cases are likely to increase dramatically in the near future. For instance, in a recent study from San Diego published in the Journal of the American Medical Association (JAMA), 141 patients who had become infected with HIV in the previous year and had received fewer than seven days of anti-HIV treatment were tested for drug resistance. Some resistance to at least one anti-HIV drug was found in 36 patients, or more than 25% of the study participants. Two percent of patients had substantial resistance to at least one drug.

In another study conducted in New York City and also published in JAMA, 80 newly HIV-infected people were tested for drug resistance. About 27% of the patients had some evidence of drug resistance, and resistance to several drugs was found in almost 4% of participants.

Although neither genotypic nor phenotypic testing is presently being used by many health care providers for this purpose, recently released federal guidelines state that use of resistance testing be considered for selecting an initial treatment regimen.

How can these tests help in choosing a new treatment regimen when an old one fails?

Drug failure is loosely defined as an increase in viral load, a decrease in T-cell counts, and/or signs of physical disease progression in people who are on combination antiretroviral therapy. Although drug failure can also be used to describe the experience of people who must stop their medication because of intolerable side effects, it is most often associated with the presence of genetic mutations and decreased drug sensitivity.

Viral-load tests are likely to remain the most important tool for determining whether or not drug failure is occurring. Drug resistance tests, on the other hand, may play an invaluable role in helping doctors and their patients understand why failure has occurred and what treatment options are still available.

[To obtain a free copy of the entire brochure, which includes a glossary and resource information, contact ViroLogic, Inc., 270 East Grand Ave., South San Francisco, CA 94080. Telephone: (800) 777-0177 or (650) 635-1100. Web site: www.virologic.com.]