HIV drug resistance occurs when microevolution causes virions to become tolerant to antiretroviral treatments (ART). ART can be used to successfully manage HIV infection, but a number of factors can contribute to the virus mutating and becoming resistant. Drug resistance occurs as bacterial or viral populations evolve to no longer respond to medications that previously worked. In the case of HIV, there have been recognized cases of treatment resistant strains since 1989, with drug resistance being a major contributor to treatment failure. While global incidence varies greatly from region to region, there has been a general increase in overall HIV drug resistance. The two main types of resistance, primary and induced, differ mostly in causation, with the biggest cause of resistance being a lack of adherence to the specific details of treatment. These newly created resistant strains of HIV may pose a public health hazard as they continue to infect a growing number of people, due to their harder treatments and continued spread within the population. For this reason, the reaction to the expanding strains of resistant HIV has mostly been to increase treatment access and implement other measures to make sure patients stay in care, as well as the attempt to develop a HIV vaccine or cure.
Mechanisms of resistance HIV is considered resistant when it no longer responds to known forms of treatment. Because currently there is no known cure for HIV, the goal of treatment is to reduce an infected individual's viral load to the point where it is no longer detectable in order to alleviate their symptoms and reduce their risk of infecting others. HIV drug resistance poses an issue because it reduces the possible HIV medications a person can take due to cross resistance. In cross resistance, an entire class of medication is considered ineffective in lowering a patient's HIV viral load because all the drugs in a given class share the same mechanism of action. Therefore, development of resistance to one medication in a class precludes the use of all other medications in the same class.
Testing for resistance A blood test can be done to determine which drugs may be effective prior to initiation of treatment or during treatment to ensure resistance has not developed. The testing may also happen again if someone's viral load increases after receiving ART. The most common kind of resistance testing is the genotypic testing of viral RNA. This method requires the patient to have a plasma viral load over 500 copies/mL to effectively sequence any existing resistant genomes. However, the test can miss resistant genomes that make up less than 5-20% of the viral population. Next-generation sequencing may catch these less frequently occurring genomes, although randomized trials have not verified the efficacy of this method.
Types of resistance
Primary resistance One type of HIV drug resistance is primary resistance. Primary resistance refers to resistance that is not incurred as a result of ART therapy. It is thought that some strains of HIV-1 are naturally resistant to ART drugs, and that the prevalence of these strains varies across the globe. Primary resistance is acquired when an individual's initial infection with HIV comes from an already resistant strain. An individual infected by a resistant strain begins their course of treatment with already limited drug options, which can pose problems later down the line if they develop additional resistance.
Induced resistance The other type of HIV drug resistance is induced resistance, which occurs as a result of drug therapy. HIV is a retrovirus that replicates quickly using reverse transcriptase, known for its lack of error correcting mechanisms, resulting in a high mutation rate. Mutations that confer substantial selective advantage to HIV survival can therefore quickly replicate within an individual, creating a new, resistant strain. These mutations accumulate over generations and in populations, resulting in the great genetic variation within populations of HIV, and an increased probability of a virion developing an evolutionary selective advantage over other virions. Natural selection then acts on HIV by selecting for virions with higher fitness, as all others are eventually killed off by drug treatments. The virions that are able to escape the harmful effects of the drug then create an entirely new, drug resistant population. The selected-for virions continue reproducing until the patient's viral load returns to pre-treatment levels, creating a cycle in which treatment is initially successful in reducing the viral load, but becomes less effective as the virus becomes resistant and virion levels once again increase. Different mutations lead to different kinds of drug resistance. Generally, the mutations prevent the drug from binding to its intended target. The prevalence of each mutation also varies. For example, induced resistance for nucleoside reverse transcriptase inhibitors (NRTIs) is more common than integrase-strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) induced resistance.
Causes of resistance
Importance of drug regimen adherence As previously described, mutations occur as a result of random mutations that are especially prevalent in HIV due to characteristic elements of the viral reproductive process, namely the use of reverse transcriptase. Several mechanisms of resistance have been identified, including mutations that block the incorporation of nucleosides, a class of HIV drug, into the viral DNA. One known cause of HIV drug resistance is lack of adherence to the prescribed drug regiment. Low levels of adherence can be attributed to lack of access to healthcare, stigmatization of HIV, and a lack of availability of drugs due to prohibitive cost or other factors. Missing doses of medication or taking them late poses a major issue because it can allow for the virus to once again begin to replicate inside the body. Proper adherence also greatly reduces the risk of the spread of the virus, thereby improving general public health and lowering health care spending. Some drugs are known to have lower incidences of resistance and may be preferable for individuals known to have difficulty adhering to a drug routine, but these benefits have to be weighed with the potential risks, including severity of side effects.
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