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HIV Drug Resistance and Resistance Testing

2001

How Do Mutations Occur Before Antiretroviral Therapy Is Started?

Mutations that occur before antiretroviral therapy is started can happen in two ways: natural selection and transmission of drug-resistant virus.


Natural Selection

Soon after HIV enters the body, the virus begins reproducing at a rapid rate (approximately 10 billion new viruses every day). In the process, HIV produces both perfect copies of itself (wild-type virus) and copies containing errors (mutated virus). In other words, there is no single virus in the body but, instead, a large population of mixed viruses called quasi-species.

When HIV reproduces, it wants to be wild-type virus. This is the most natural and usually most powerful form of the virus and, as a result, reproduces the best. Before antiretroviral therapy is started, wild-type virus is the most abundant in the body and dominates all other quasi-species in the body.

When HIV makes mistakes during copying, mutated viruses -- called variants -- are produced. Some variants are too weak to survive and/or cannot reproduce. Other variants are strong enough to reproduce but still are not able to compete with the more fit wild-type virus. As a result, their numbers are less than wild-type virus in the body.

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Some variants have mutations (sometimes called polymorphisms) that allow the virus to partly, or even fully, resist an antiretroviral drug. This is why people living with HIV should never take just one antiretroviral drug (monotherapy). For example, HIV only requires one mutation -- M184V -- to become completely resistant to Epivir. The same goes for the non-nucleoside reverse transcriptase inhibitors Viramune, Rescriptor, and Sustiva. The K103N mutation can cause the virus to become highly resistant to these three drugs.

These HIV mutations occur randomly and there is no proven way to prevent them from occurring. Variants containing these mutations usually don't go on to develop additional mutations; doing so compromises their ability to stay alive in the body. So while these variants may be completely resistant to one antiretroviral drug, they are almost always sensitive to other drugs used in a regimen. This is why three-drug regimens work better: a variant may be resistant to one of the drugs but doesn't stand much of a chance when facing two other drugs that bind to different parts of the virus.


Transmission of Drug-Resistant virus

This is a growing problem and is being reported by many researchers.

Many HIV-positive people now take or have taken antiretroviral therapy. If someone has developed resistance to one or more of the antiretrovirals and has unprotected sex or shares needles with someone who is not infected with the virus, it is possible that they can infect their partner with a drug-resistant variant -- a strain of HIV containing mutations that cause resistance to one or more antiretroviral.

An example: Person A is HIV-positive and has been taking a triple-drug antiretroviral regimen consisting of Crixivan, Retrovir, and Epivir. He does not know it, but his virus contains mutations associated with resistance to these three drugs. He has unprotected sex with Person B, an HIV-negative woman. Person A's virus enters Person B's body and begins reproducing. The end result is that Person B has been infected with a multiple-drug-resistant (MDR) variant of HIV.

At first, the MDR variant in Person B's body would dominate all other viruses that are produced during copying. Over time, wild-type virus will emerge and usually dominates the MDR variant. But this does not mean that the MDR variant is gone; it has merely become a minority member of the entire population of HIV.

If Person B were to start therapy a few years later with Crixivan, Retrovir, and Epivir, the wild-type HIV would diminish quickly, but would probably be replaced with the MDR variant already in her body. As a result, Person B might have a difficult time reducing her viral load or keeping her viral load undetectable.

According to some studies, between 10% and 30% of all new HIV infections (defined as people infected with HIV over the past two years) involve strains resistant to at least one antiretroviral drug. Some researchers expect that this percentage will increase in the years to come.

It might also be possible for someone who is already infected with HIV to be infected, again, with a (multiple) drug-resistant strain of HIV. This is sometimes referred to as reinfection or superinfection. There has been at least one report demonstrating that this may be 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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