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Mapping Out Your Treatment Journey
A Look at Resistance Testing

By Frank Pizzoli

March/April 2000

If you don't know where you're going, any road will take you there.

Sixteen anti-HIV drugs are now available. Another dozen agents are projected for review by the Food and Drug Administration (FDA) in the next several years. Beginning or maintaining HAART (highly active anti-retroviral therapy) is a journey made less risky -- but not risk free -- by advances in genotype (GT) and phenotype (PT) resistance tests.

Not yet FDA approved, these tests can potentially identify drug regimens that would be more effective for a particular person. The idea is to establish a "sequencing" of drugs in order to maximize available drugs' anti-HIV qualities and prolong treatment benefits for as long as possible. While the test results are useful, neither test can tell with certainty who will gain the most benefit from particular drug combinations.

Genotype testing determines any changes, called mutations, to the part of HIV's genetic structure that makes key proteins. Viral samples are inspected for the presence of specific viral mutations known to be resistant to certain drugs. The reverse transcriptase gene is the target for nucleoside analogs (Hivid, Videx, Zerit, Epivir, Ziagen, and Retrovir, or AZT) and non-nucleoside analogs (Rescriptor, Sustiva, and Viramune). The protease genes are attacked by protease inhibitors (Agenerase, Crixivan, Fortovase, Invirase, Norvir, and Viracept).

Phenotype resistance is a more direct measure of viral resistance to specific HIV drugs. It examines the amount of drug needed to inhibit HIV growth. In its natural state, HIV is a "wild type virus" and is usually not resistant to particular HIV drugs. This allows them to suppress replication of the virus. Resistant virus requires higher levels of existing drugs to achieve an equal amount of suppression.

Both tests identify genetic HIV sequences in an individual's blood samples and then compares them to a "registry" that holds the "true" genetic HIV sequence. Deviations from the "true" sequence correspond to resistance to certain HIV drugs. Knowing these differences is important information when people begin treatment or for those whose drug combination has become resistant to their regimen. In a perfect world, people would combine GT to establish the specific "type" of virus in their blood with PT to determine the effective "amount" of particular anti-HIV drugs they need to take.


Just Beginning

Individuals beginning HAART face challenging decisions: to begin with or delay the use of protease inhibitors or non-nucleosides, or both. Resistance testing might be especially useful in helping individuals identify if their viral type is responsive or resistant to PIs or NNRTIs, and which ones.

Resistance tests also help individuals identify if they have been infected with a virus already resistant to antiretrovirals. The possibility for this is higher in cities like New York or San Francisco where many people have been treated extensively, and may therefore be shedding a "mutated" virus. Resistance tests can be done before treatment starts to avoid using drugs that are unlikely to be effective.

Likewise, with needlestick exposure or possible maternal transmission, the virus may be tested to ensure it is not already resistant to certain drugs. Of course, treatment may need to begin before test results are available.

Although these tests may help with treatment decisions, individuals must carefully compare their own HIV history and characteristics with known treatment outcomes. For example, results from Merck Study 035 indicate that success with PIs in first-line treatment is durable: 30 patients received Retrovir (AZT) with Epivir and the company's protease inhibitor Crixivan for three years, and 20 of the 30 still have a viral load below 50 copies.

Another study concluded that PI-containing regimens "had a greater effect on the lymph nodes than those containing nucleoside analogs alone despite comparable levels of suppression" of HIV. Although these regimens are durable for study participants, this combination may not be able to fight down all viral types, making resistance testing an attractive choice.

Other results show that individuals on PIs may have HIV levels rebound after achieving undetectable viral loads, but that this virus causes less immune destruction. This explains why individuals whose viral load rebounds on PIs do not always experience declining CD4 cell counts. Individuals whose resistance tests indicate PI effectiveness may want to begin with a PI combination, hoping to diminish the virus's strength over time.

Although many clinicians consider PIs optimal first-line therapy, it is possible to lower viral load without their use. If an individual's unique HIV genetic code isn't resistant to non-PI drug combinations, a protease-sparing regimen may be useful in controlling viral load. This approach saves PIs for future use, if and when individuals become resistant to an initial drug combination.


Experienced Individuals

In several retrospective studies (looking back at what happened) of treatment-experienced people, baseline GT and PT results predicted response to new therapy. Although prospective studies are still needed, these results begin to validate the tests' usefulness. For example, when a combination treatment fails to control the virus, a resistance test may help decide what new combination might work. In this scenario, the test must be done while the patient is still taking the failing drugs, since without the drugs resistant virus is likely to be replaced by the original non-resistant virus. It then declines to very low levels that the tests will not detect. Yet, the virus will be ready to come back almost immediately if the drug is started again.

Keep in mind that recent studies suggest that PI resistance may not be an issue for individuals who experience viral rebound while on PI-containing regimens. The predominant virus that rebounds is often resistant to the other drugs in the combination, but not the PI. In this case the other drugs can be switched or another drug added as an attempt at therapy "intensification." This is a classic example of how resistance testing might be used to identify and monitor particular drug sequences.


The Next Round

People with drug resistance have a lot of variables to wrestle with. For example, someone is taking all their drugs on schedule and observing food requirements, and yet the regimen has failed. Assuming that you are absorbing enough of the drug to get an effective level in the body, the most likely cause of drug failure is antiretroviral resistance.

If resistant, the "next round" of drugs will depend heavily on previous drug exposure and likely include a PI or two, and an NNRTI, or both. Several studies show success with the inclusion of an NNRTI in subsequent regimens, especially if someone has never taken an NNRTI. For example, one study showed that these people achieve lower HIV viral loads at 24 weeks than do patients who have previously used an NNRTI. The small sample also indicated that 83% of the NNRTI-naive individuals see a 0.5 log decrease in viral load while only 66% of NNRTI-experienced people see the same result. The use of more PI-sparing regimens as first-line HAART may allow for NNRTI-naive individuals to have a reasonable chance at treatment success when searching for the next combination.

Please note that NNRTIs originally were thought by most to have less antiviral potency and durability when compared with the PIs. On-going trials are calling into question those assumptions. The DuPont 006 study now has 48-week data showing that patients who start with high viral loads (over 100,000 copies) can have sustained viral suppression on a protease-sparing regimen of the company's non-nucleoside analog drug Sustiva in combination with AZT/Epivir. Consequently, resistance testing may be vital for individuals whose drug treatment plan is failing in order to properly identify remaining drug combination choices.

Because individual reactions and resistance to various drug regimens vary widely, physicians familiar with the tests warn that using the tests to identify remaining useful anti-HIV drugs is best done "sooner" than "later."


Pros and Cons

GT is a less complex, less expensive test ($300-$500 per test) with results more rapidly available. Beware that some mutations counteract each other, so results may not be able to truly determine drug resistance. For drug-resistant individuals who have stopped therapy, GT may still be able to identify mutant virus. This test may be more accurate for nucleoside analogs and non-nucleoside analogs, and less useful for PIs that do not always show consistent mutation patterns. For accurate GT results, viral load must be above 1,000 copies.

PT is a more complex, more expensive test ($800-$1,000) with results taking longer than GT. On the plus side, HIV mutations are generally interpretable for all anti-HIV drugs. PT results work best with a viral load of 5,000 copies.

So, resistance testing can be used either to select the best initial therapy or to realign existing therapy. When you decide you're ready to rumble with HIV, perhaps GT and PT may help you go a few extra rounds in the ring.

Freelance writer Frank Pizzoli is founder and executive director of Positive Opportunities in Harrisburg, Pennsylvania, an HIV-employment service where drug choices, effectiveness and adherence really matter.




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