The Antiviral Drugs Advisory Committee (ADAC) to the Food and Drug Administration (FDA) recently held a two-day meeting to discuss HIV drug resistance testing. The discussion centered on currently available results from drug resistance tests and not on any one specific test or drug. For more information on HIV drug resistance and resistance testing, call Project Inform's Hotline and ask for the Geno- and Phenotypic Resistance Tests Quick Sheet.
The ADAC recommended that companies submitting anti-HIV drug approval applications should include resistance data as part of their package to the FDA. More data will be required if companies want to claim their drug is effective against virus that is resistant to other drugs.
All ADAC members agreed that resistance testing had a role in drug development and that both genotyping and phenotyping are important tools for making treatment decisions. The ADAC suggested that, when appropriate, resistance testing should be performed on all participants at study entry and at the time of viral load rebound (when viral load becomes detectable or starts increasing again). This would help to better understand how a drug combination performs in the presence of drug-resistant virus and also the effect of new or added drug resistance on other anti-HIV drug regimens.
Ideally, the resistance testing should be performed in real time -- that is, people should get the results within three to four weeks so they may act quickly on the information. Unfortunately, many studies prefer to batch all their resistance testing together at fixed time points. This approach may be easier for the researchers and might even slightly increase the accuracy of the results, but the outcome is far less useful to the study volunteers. A growing number of people get these tests done on their own outside of a study as a way to select an optimal regimen and to know when to switch regimens without waiting for the end of the study. If real time resistance testing is not routinely included in studies, then people may simply choose to get it independently. Researchers, however, fear that people who get their own results in real time may be more likely to drop out of studies when their regimens fail or show signs of resistance.
One area of contention between drug developers and resistance test developers is the level of drug resistance that should be considered significant. Currently, most people consider a four-times decrease in sensitivity to the drug to mean low-level resistance and anything above a ten-times decrease to mean high-level resistance.
This has generally been considered acceptable because the amount (level) of drug measured in a person's blood is usually four to eight times higher than what is needed to simply block HIV replication. It is usually not possible to increase the dose of a drug much beyond this because this will also increase the number and severity of side effects.
However, as we move toward using combination protease inhibitor therapies -- especially using ritonavir (Norvir) to boost the amount of drug found in blood (see "First Line: Indinavir/Ritonavir" in this issue) -- these standard four times and ten times changes may become irrelevant. With some drugs and combinations, it is possible to safely achieve much higher drug levels (15 or more times higher than needed to block HIV replication) and potentially overcome some viruses with low-level resistance, even though test results indicate you may be resistant to one or more of these drugs. The ADAC recommended that the amount of resistance to a drug that renders it ineffective should be determined for each individual drug, rather than having a single standard apply to all drugs.
Several studies show that resistance testing can determine which drugs in a regimen no longer work. But few studies show that resistance testing can predict the success of a new regimen. Currently, resistance testing provides little-to-no information on the durability of a new regimen.
New preliminary results presented at the ADAC meeting show that resistance testing can predict short-term response to a new drug. Virco, developers of Antivirogram® phenotypic and VircoGen® genotypic tests, conducted this study. The phenotypic test was used on 274 people with a viral load of at least 2,000 copies HIV RNA who were taking at least two nucleoside analogue drugs and one protease inhibitor.
Half the participants received immediate phenotypic testing and could change therapies based on all available information (treatment history, viral load and CD4+ cell counts) plus the results of the phenotypic testing. The other half had delayed phenotypic testing results and could change therapies based only on the other available information.
After 16 weeks, the group with immediate testing had much better anti-HIV therapy responses. Their average viral load decreased by 20 times (about 1.3 logs) while the delayed testing group's average viral load only decreased by four times (about 0.6 logs). This ongoing study should provide information on the durability of response to a regimen selected on the basis of resistance test information.
In the near future, resistance testing is likely to become part of standard of care in managing HIV. Currently many third-party payors are not reimbursing for these tests. Consumer and community pressure for payment warrants action.
Resistance testing can help people living with HIV and their healthcare providers make better treatment decisions. Other needed tools are tests for monitoring anti-HIV drug levels in blood, commonly called therapeutic drug monitoring. Increasingly, studies show that people who achieve higher sustained drug levels in their blood have better and more sustained anti-HIV responses.
There are many different factors to consider when measuring how each persons' body breaks down drugs. These factors often result in varying levels of drugs in the blood stream, even for patients who are taking the same dosages. Therapeutic drug monitoring may make it possible to ensure a good and lasting anti-HIV response. Achieving the ideal dose makes it more difficult for the virus to develop resistance. However, the feasibility of adding blood level monitoring to the already complex and costly practice of AIDS medicine is in doubt.
The developers of genotypic and phenotypic tests need to make them more affordable and guarantee a rapid turnaround for results. Genotypic test developers also have to ensure that the results they produce and send back to healthcare providers include quality interpretation and guidance for using them.
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