10 Things You Should Know About HIV Drug Resistance

1
Antiretroviral Drugs Do Not "Make" HIV Resistant.

Image © James Myhre, 2013.

When an HIV infection occurs, it is not with a single type of HIV but with a pool of thousands of different types (or "variants") of HIV.

Drug resistance is caused when the ecological environment of the viral pool is changed. When antiretroviral drugs are added to the pool, the viruses most able to survive take precedence over those that can't. These are the "resistant" viruses.

Over time, these resistant viruses can become the predominant population. This can be a naturally occurring event which develops slowly over time. In many cases, however, drug resistance develops treatment is either stopped or interrupted, allowing the resistant variants the opportunity to thrive.

2
"Wild-Type" HIV is Generally the Predominant Variant At the Time of Infection.

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Within the viral pool, "wild-type" HIV is simply the predominant type of HIV which has not yet mutated. It is also considered the most "fit" variant and, therefore, best able to survive in its natural (untreated) state.

In most cases, wild-type HIV predominates over all other variants. It not until the viral pool is exposed to antiretroviral drugs that the make-up of the population begins to change.

3
Why Are There So Many HIV Variants?

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If left untreated, HIV replicates prolifically, producing as many as 10 billion new viruses every day. But at the same time, HIV is highly prone to genetic errors when replicating. The viruses produced by these mistakes are called "mutations."

"Mutation" does not inherently mean "resistant." The vast majority of mutated HIV is so distorted that it is unable to sustain itself and therefore completely harmless, unable to infect CD4 cells and, therefore, unable to reproduce.

Occasionally, a mutation can result in a drug resistant variant. This can occur naturally even before the start of antiretroviral therapy. However, these variants are far less "fit" than wild-type virus and are unable to compete in an untreated viral pool. Their presence at this stage rarely relates to any level of drug resistance.

4
The Presence of a Resistant Variant Does Not Mean You are Resistant.

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Resistance is measured in degrees. A resistant variant may have "partial resistance," "possible resistance," or be fully "susceptible" to antiretroviral therapy.

For a high-level resistance to develop, a virus needs to go through a series of genetic "mistakes" that give it the survival advantage. In an untreated pool—where competition is fierce and wild-type tends to dominate—resistant viruses have little chance to compete.

The goal of antiretroviral therapy is to keep all variant populations fully suppressed. In doing so, variants with possible or partial resistance are inhibited from mutating further. Optimal drug adherence reduces the ability of a virus to become fully resistant.

5
Resistance Can Be "Transmitted" From One Person to the Next.

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If drug resistance is detected in a new infection, it is almost always "transmitted"—that is, passed from a person who has resistant HIV—either through unprotected sex, shared needles, transmission from mother to child, etc.

According to research from the U.S. Centers for Disease Control and Prevention (CDC), 20% of new infections in the U.S. involve a transmitted resistance to one or more antiretroviral drugs.

Post-exposure prophylaxis (or PEP) has been shown to significantly reduce the risk of transmission in the event of accidental exposure.

6
Resistance Testing Helps Determine the Right Drug Combination For "Your" Virus.

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Resistance testing provides your doctor with a picture of the types (and levels) of drug resistance, if any, that you may have prior to the start of antiretroviral therapy.

By identifying the types of resistance you have, your doctor can choose the best combination of drugs to stop the replication of HIV in your body. Together, the combined medication is better able to inhibit replication of partially resistant viruses than a single drug can.

7
Suboptimal Adherence Gives Resistant HIV the Survival Advantage.

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Wild-type HIV may be the most "fit" variant, but it is also the most susceptible to antiretroviral drugs. In short, wild-type is the first to go when antiretrovirals are introduced into your body.

Suboptimal drug adherence—due to missed doses or interruption of therapy—allows for drug serum levels to drop in the bloodstream. As levels drop, otherwise inert populations of resistant virus are given the chance to replicate. Unless adherence can be corrected, these variants will eventually predominate.

8
Additional Mutations Can Increase the Levels of Drug Resistance.

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Drug resistance doesn't happen all at once. It develops gradually over time as additional mutations increase the "fitness" of the resistant population.

If HIV is not fully suppressed, the resistant variants will continue to mutate. With each generation, additional changes in the genetic code can increase their resistance until a drug no longer has any effect. This is called "treatment failure."

If a treatment failure occurs, it is unwise to continue. This only allows for additional mutations to develop. Treatment should be reviewed with your doctor and changed accordingly.

9
Resistance to One ARV Can Lead to Cross-Resistance.

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Because resistance relates to changes in the virus's genetic coding, any mutation that causes resistance to one drug can cause resistance to other drugs of that class. This is called "cross-resistance" and is particularly seen among non-nucleoside reverse transcriptase inhibitor (NNRTI) class drugs.

At times, a single change in the genetic code can confer complete resistance to some drugs. But in most cases, high-level drug resistance requires multiple mutations—up to 10 and even more with newer generation antiretrovirals.

10
Resistance is Not Futile, But It is Forever.

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Once you have a resistant virus, you will always have that resistant virus. And as that virus passed from one person to the next, it can continue to build resistance upon resistance. Newly infected people may suddenly find themselves with limited treatment options, while the re-infected may be less able to maintain viral suppression even with full adherence.

Optimal drug adherence and safer sex practices are key not only to reducing transmission, but to prolonging the viability of your drugs over the long term.

Sources:

Ocfemia, C.; Kim, D.; Ziebell, R, et al. "Prevalence and Trends of Transmitted Drug Resistance-associated Mutations by Duration of Infection among Persons Newly Diagnosed with HIV-1 Infection: 5 States and 3 Municipalities, US, 2006 to 2009." 19th Conference on Retroviruses and Opportunistic Infections (CROI). Atlanta, Georgia. March 7, 2012; poster abstract #730.

De Meyer, S.; Vangeneugden, T.; Van Baelen, B, et al. "Resistance profile of darunavir: combined 24-week results from the POWER trials." AIDS Research Human Retroviruses, March 2008; 24(3):379-88.

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