Your next nightmare: 28% of new HIV cases may be drug-resistant
You must test to identify these cases for special treatments
At the advent of 2000, HIV clinicians are predicting that AIDS cases, which have been dropping for the past five years, will rise as increasing numbers of HIV-infected people are unable or unwilling to adhere properly to their drug regimens, allowing resistant strains to emerge. Consequently, clinicians must find ways to make the current drugs work better and longer through standard resistance testing of HIV in new and established patients.
The virus is beginning to regain the battlefield through its rapid mutations and increasing ability to thwart even the stealth bombers of protease inhibitors. AIDS researchers have discovered that nearly 28% of people who are newly infected with HIV may have become infected with a virus that is resistant to one or more antiretroviral drugs.1,2
"There is no question that as we have more people who have been treated for a longer period of time on a wider variety of drugs, resistance is becoming more of an issue," says Robert Schooley, MD, head of the infectious disease division of the University of Colorado in Denver.
And within the next year, Robert Murphy, MD, professor of medicine at Northwestern University in Chicago, predicts there will be universal use of drug resistance tests.
Before the introduction of genotyping and phenotyping assays for detecting drug-resistant HIV, clinicians didn’t have to pay much attention to viral mutation because there was no way to measure it. Now that these tests are available, and with some groups providing guidelines for their use, they will become the standard of care for HIV patients, Murphy says.
"This will change things for clinicians because there will be no more blindly changing from drug A to drug B or from regimen A to regimen B," he adds.
Researchers are finding greater evidence that HIV is rebounding in patients receiving long-term antiretroviral therapies, which suggests drug resistance is on the rise, according to studies presented at the 39th Interscience Con fer ence on Antimicrobial Agents and Che mo therapy (ICAAC), held in San Francisco in September.
However, the good news presented at ICAAC was that drug manufacturers are making strides in keeping ahead of drug-resistant strains. For example, Joseph Eron, MD, presented data on a new protease inhibitor, ABT-378. The combination of this drug with ritonavir showed efficacy in patients who have HIV that is resistant to one or more protease inhibitors.
"We clearly demonstrated that at least two-thirds of all patients who entered the trial had failed a protease inhibitor," says Eron, who is the co-director of AIDS Clinical Research in the Infectious Disease Division of the University of North Carolina at Chapel Hill.
The ABT-378/ritonavir study shows that 78% of the patients who had been on other antiretroviral medications, including those who developed resistance to the other drugs, experienced viral suppression on ritonavir. (See story on ABT-378/ ritonavir study, p. 136.)
Just as drug susceptibility testing is routine in choosing antibacterial drugs, so will it become standard in choosing HIV drugs, predicts Daniel Kuritzkes, MD, associate professor of medicine and microbiology at the Division of Infectious Diseases, University of Colorado Health Sciences Center in Denver.
"The concept of doing resistance testing for viruses is not that new," Kuritzkes adds. "What’s new is the technology that makes it feasible to do this on a commercial scale for HIV."
A variety of research has been published in the past 18 months demonstrating how resistance testing will help with clinical management, says Richard D’Aquila, MD, associate professor of medicine for Harvard Medical School and Massachusetts General Hospital in Charlestown.
"Specifically, resistance testing seems to be able to help in choosing which drugs should be in a regimen, particularly when drug combination regimens are failing and the physician wants to start a new regimen," D’Aquila says.
"The data is quite consistent from all different studies that resistance testing will help you choose drugs that are more active against the virus," he adds.
The fact that resistance testing is even necessary for HIV is another reason why clinicians who treat HIV patients should be experienced with the disease and treat many HIV patients, Kuritzkes says. "Resistance tests as a whole are another example of how complicated it’s becoming to manage HIV-infected patients and to appropriately prescribe and manage modern antiretroviral therapy."
Now research is needed to study the best ways to use resistance testing for the purpose of helping physicians make clinical decisions, Schooley says.
"We already know a lot about what particular resistance pathways individual drugs push the virus down, and the genotypic and phenotypic tests confirm this in clinical practice," Schooley says. "We already know that if you have a patient who has a virus that is measured as being resistant to a given drug, then it’s unlikely the drug will have an impact on the virus in that patient."
But where do clinicians go from there? For example, researchers need to learn which mutations are the best predictors of resistance in particular situations and how much resistance is acceptable for a drug to continue to work.
The chief problems with resistance testing involve interpreting test results and making clinical decisions based on the results, as well as a multitude of other factors, D’Aquila says.
"The tests are pretty good and they should improve, but there are several problems that are mostly due to the biology of HIV," D’Aquila says. "In the hands of experienced clinicians, it still can be useful for making judgments about which drugs may be relatively better than other drugs."
Once additional clinical research into resistance testing is completed, then resistance tests will become more useful, and clinicians will know better when to use a certain type of resistance test.
Kuritzkes and other experts describe the types of resistance tests now available to clinicians:
• Genotyping. This can be done by one of several different sequencing methods. The process uses an indirect method of testing for resistance by searching for genetic mutations that are known to signify resistance. It involves determining the nucleotide sequence of the protease or reverse transcriptase genes, Kuritzkes explains.
A study of a genotyping test manufactured by Visible Genetics Inc. of Toronto, Ontario, recently published in The Lancet, shows that genotypic resistance testing has a significant benefit for virological response when choosing a therapeutic alternative.3 Specifically, researchers conclude that genotypic resistance testing helps clinicians make decisions about treatment changes, based on their findings that the percentage of patients with HIV-1 RNA lower than the detection level was better in the genotypic group than in the control group.
About 32% of the patients who were tracked with Visible Genetics’ TruGene HIV test had undetectable levels of HIV, compared with only 13.9% of the patients who were treated according to current standards for triple-drug selection.
"For genotyping information to be useful, we really need to know a lot in advance, such as which mutations are responsible for resistance," Kuritzkes adds.
Accuracy varies with genotyping tests
Genotypic assays have no standard, and the accuracy of results, which may take up to six weeks to obtain, varies from lab to lab. Plus, labs may miss new mutations and resistant strains.
For example, investigators working in the Netherlands sent panels with HIV that has protease inhibitor-resistant mutations and others with virus that has reverse transcriptase inhibitor-resistant mutations to 33 labs. The labs had difficulty detecting drug-resistant virus in the panels that had 50% or fewer drug-resistant mutations. Fewer than half of the labs were able to detect resistance in these populations.4
Then there is the problem of interpreting test results, even when they accurately detect drug-resistant virus.
"The downside of genotypic testing is you don’t always know how to predict what a genotype means in terms of true sensitivity of the virus," Schooley says. "There are ambiguities in terms of protease inhibitors that can cause you to overpredict or underpredict resistance, although complex databases are making this better."
So the companies that designed the tests have developed genotyping kits with reports that interpret the information for physicians.
"Of course, this is very tricky because there’s still a lot that is not known on genotyping," Kuritzkes says. "You need to generate reports that provide the assay result and make some judgment about what drugs are likely to be useful, without making a treatment recommendation."
Clinicians then review the reports and decide whether to discontinue current drug therapy based on what the results show.
• Phenotyping. This is a much more complicated process and currently is conducted by two labs: ViroLogic in San Francisco and Virco in Belgium. ViroLogic’s test, called PhenoSense HIV, can provide individualized drug susceptibility information in two weeks.
Phenotyping works by directly measuring the sensitivity of a patient’s virus to all antiretroviral drugs. Specifically, it involves amplifying the reverse transcriptase and protease genes of a patient’s virus, using polymerase chain reaction testing, and then inserting these into a backbone that contains the other HIV genes to create recombinant viruses. Everything about the viruses is identical except for the protease and reverse transcriptase genes that come from a specific patient. Then the recombinant viruses are tested for their ability to grow in the presence of varying concentrations of the currently available drugs, Kuritzkes explains.
"But to do this in an efficient and cost-effective way requires very extensive automation and all kinds of robotic machinery, and because of that the set-up is quite complex and not easily transferred to local hospital labs," he adds.
On the plus side, phenotyping tells clinicians whether a virus is sensitive to any particular drug, including protease inhibitors, which tend to have overlapping mutations.
For example, suppose a patient has been treated with indinavir and has some HIV mutations that are resistant to some protease inhibi tors. The genotype test will show that this resistance exists, but it won’t discern which drugs this resistant virus may not affect. The phenotypic test, however, will show that the virus is resistant with two-thirds of the drugs, but one-third remains sensitive. This way, the clinician may pinpoint exactly which protease inhibitors will continue to work in suppressing the virus.
A study presented at the September ICAAC conference shows that phenotypic HIV drug resistance testing works better than obtaining treatment history in predicting sustained HIV suppression during antiretroviral therapy.5
Another recent phenotyping study shows that ViroLogic’s phenotypic drug susceptibility assay can detect drug resistance to a three-drug combination therapy before the virus load rebounds. The same study found that phenotypic testing is more reliable than genotyping testing as a predictor of how a patient responds to therapy.6
When phenotyping and genotyping are compared, researchers have found that phenotyping is more accurate in detecting drug-resistant virus. A study led by Martin Markowitz, MD, of the Aaron Diamond AIDS Research Center in New York, found that genotypic testing identified drug-resistant virus in 85% of the cases that phenotypic testing determined to have reduced susceptibility.2
Phenotyping has its own problems
Although phenotyping has proven to be very accurate, it still poses problems when used in a clinical setting, Schooley says.
"The difficulty is, we don’t know exactly how to extrapolate all those data to make clinical decisions, and that’s where a lot of the research now is being focused," he explains.
Clinicians may receive some answers to their questions about interpreting resistance testing results early in 2000, when guidelines are expected to be published by the Interna tional AIDS Society USA of San Francisco, says Kuritzkes, who is part of a panel that is working on the recommendations.
"We hope to publish a set of guidelines for interpreting resistance tests and their appropriate clinical use," he says. "Also, I’m sure the updated [antiretroviral] treatment guidelines will have a major emphasis on avoidance of resistant virus."
References
1. Little SJ, Daar ES, D’Aquila RT, et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA 1999; 282:1,142-1,149.
2. Boden D, Hurley A, Zhang L, et al. HIV-1 drug resistance in newly infected individuals. JAMA 1999; 282:1,135-1,141.
3. Durant J, Clevenbergh P, Halfon P, et al. Drug-resistant genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 1999; 353:2,195-2,199.
4. Schuurman R, Brambilla DJ, De Groot D, et al. Second worldwide evaluation of HIV-1 drug resistant genotyping quality, using the EVNA-2 panel. Abstract 1168. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco: Sept. 26-29, 1999.
5. Saag M, et al. Predictive value of HIV phenotypic susceptibility testing in an HIV clinical cohort. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco: Sept. 26-29, 1999.
6. Parkin NT, Lie YS, Hellmann N, et al. Phenotypic changes in drug susceptibility associated with failure of human immunodeficiency virus type 1 (HIV-1) triple combination therapy. J Infect Dis 1999; 180:865-870.
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