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HIV Drug Resistance and Resistance Testing

2001

How Do Mutations Occur During Antiretroviral Therapy?

Soon after antiretroviral therapy is started, the amount of virus in the body is reduced dramatically. Unfortunately, no antiretroviral drug -- or combination of drugs -- is able to completely stop HIV from reproducing. In other words, there is always a small population of virus in the body that continues reproducing, despite the presence of antiretroviral drugs.

As discussed in "How Do Mutations Occur Before Antiretroviral Therapy Is Started?, there is a large mixture of virus in an HIV-infected person's body. Antiretroviral-drug therapy reduces the amount of all HIV quasi-species in the body. The amount of wild-type virus is dramatically reduced, and the number of variants is also decreased.

Wild-type virus is the most sensitive to antiretroviral drugs. Because of this, HIV variants in the body have a survival advantage over that of wild-type virus. In the presence of antiretroviral drug therapy, variants can become the dominant strain of HIV, even though there is a much smaller amount of HIV in the body.

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Over time, variants accumulate additional mutations. Some of these mutations will harm the virus, while others will further limit a drug's ability to stop it from reproducing. Once the virus has accumulated enough mutations, the antiretroviral drugs lose their ability to bind to it and prevent it from reproducing. As the drugs become weaker, the amount of drug-resistant virus in the body increases, causing an undetectable viral load to become detectable again and increase over time. If the drug-resistant virus continues to reproduce, it can acquire even more mutations to resist the antiretroviral drugs completely.

Mutations that emerge during therapy can be divided into two groups: primary mutations and secondary mutations. Each antiretroviral drug is associated with at least one primary mutation. Primary mutations are of greatest concern, as they are the ones that cause the greatest amount of drug resistance. Secondary mutations do not cause drug resistance unless a primary mutation is present. If both primary and secondary mutations are present, drug resistance can become more complicated.

While primary and secondary mutations can cause the virus to become resistant to anti-HIV drugs, they usually have a negative effect on the power of the virus. This is why some people who are experiencing an increase in their viral load might not see a decrease in their CD4+ cell counts, at least not at first. In other words, the virus loses its ability to cause damage to the immune system if it contains drug-resistance mutations. However, some studies show that certain primary and secondary mutations can cause the virus to regain its power and, quite possibly, become even more powerful than wild-type virus. Because of this, most experts recommend switching therapies before the virus accumulates any additional mutations.

Cross-resistance can also occur during therapy. When HIV becomes resistant to one drug, it can automatically become resistant to other drugs in the same class. For example, the primary and secondary HIV mutations that occur in someone who is taking the protease inhibitor Crixivan are the same mutations that cause resistance to the protease inhibitor Norvir. Even though the person hasn't yet taken Norvir, he or she will likely be cross-resistant to the drug and will not likely benefit from it.

The key to avoiding the accumulation of mutations that cause resistance and cross-resistance is to keep the amount of virus in the body as low as possible, for as long as possible.




  
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This article was provided by AIDS Community Research Initiative of America. Visit ACRIA's website to find out more about their activities, publications and services.
 

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