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Being Alive
An Update on Antiviral Resistance
Mark Katz, MD; reported by Jim Stoecker
May 5, 1997
Being Alive 1997 May 5: 3

Last month, we reviewed the current thinking on when to start antiviral therapy, what antivirals to start with and when to change your antiviral regimen. Left open was the question of why antiviral regimens fail to suppress the virus. The most likely cause is the development of viruses that are resistant to the drug or drugs being used. In fact, we suspect the development of resistance whenever an antiviral regimen results in incomplete suppression of hiv.

Two Types of Resistance Scientists talk about two types of antiviral resistance. Phenotypic resistance refers to the decreased susceptibility of hiv to the drug being used. This is the practical definition of resistance, what most of us mean when we talk about antiviral resistance. The drugs aren't working because most likely the virus has mutated in such a way that the drug no longer is fully effective.

Genotypic resistance refers to those mutations which are associated with the emergence of phenotypic resistance. This is the actual specific genetic mutation of the virus and is of interest to scientists and researchers. Today we have sophisticated testing mechanisms that can type the particular hiv that infects an individual. This testing can determine whether genotypic resistance is present, whether specific mutations of the virus exist in the blood. No test, however, will tell whether resistance is actually occurring.

With a viral typing test, we may know that an individual is at risk for developing resistance to certain antivirals, but the actual emergence of resistance must be inferred from viral load testing and the monitoring of the individual's overall health.

Reverse Transcriptase Inhibitors The reverse transcriptase inhibitors have differing resistance patterns. AZT resistance emerges gradually because a combination of several viral mutations are required for high level resistance. The risk of developing AZT resistance increases with time on the drug. Time allows the virus to form the specific set of mutations required.

On the other hand, both 3TC and nevirapine have a single point mutation that confers high level resistance to the drug. This means only one viral mutation is required to highly reduce the effectiveness of these drugs. In fact, early testing of nevirapine revealed the rapid development of resistance when the drug was used alone. Nevirapine is now used only in combination with other antivirals. Some researchers are suggesting that the use of both 3TC and nevirapine be avoided when prescribing a first-time antiviral combination. They reason that since these drugs require only one mutation to render them ineffective, their use should be confined to later combinations. Such an approach, however, is not part of the current standard of care.

The "d" drugs (ddI, ddC and d4T) all have low levels of phenotypic resistance. This means that should genotypic resistance occur, these drugs are not rendered totally ineffective. Even if the required viral mutation occurs, these drugs retain some efficacy. Because of this, certain researchers would recommend that these be the drugs for an intial antiviral regimen.

Protease Inhibitors Early studies on protease inhibitors highlighted the importance of dosage level and regimen compliance in the development of resistance to these antivirals. For example, early studies of saquinavir showed less viral mutations when 7200 mg per day were used versus 3600 mg per day. Equally important is staying with the recommended dosing schedule, which ensures that adequate levels of drug are present in the bloodstream, thereby lessening the development of viral mutations.

With protease inhibitors, we have the additional issue of cross resistance. If you develop resistance to one protease inhibitor, are you then resistant to the others? This appears to be the case with saquinavir, indinavir and ritonavir. However, early studies of the newest protease inhibitor, Agouron's nelfinavir, suggest that if you become resistant to it, you may still be sensitive to the other currently-available protease inhibitors.

Strategies for Avoiding Antiviral Resistance We know that resistance is more likely to occur if there is incomplete suppression of the virus. In such a case, the virus continues to reproduce and mutate. The specific mutations required for resistance can begin to emerge. Thus, the best way to avoid the emergence of resistance is to go for complete suppression of the virus. (As we mentioned last month, this is in fact the goal of any antiviral regimen.) This means that you determine the most powerful combination of drugs available, that you take the highest recommended dosage, and that you follow the dosing schedule accurately and completely. If resistance should emerge, you then determine a new regimen to suppress the virus. The good news today is that we have a number of antivirals available to develop the best possible regimen for each individual.