Antiretroviral Therapy
(Part XXV)

General Mechanisms of Resistance

HIV variability represents the most important factor in the emergence of resistant strains. The high rate of HIV replication throughout the course of the infection and the occurrence of many mutations during each replication cycle because of the inaccuracy of reverse transcriptase (a phenomenon common to all single- stranded RNA viruses) are the basis for the emergence of drug- resistant variants under the selective pressure of antiretrovirals. In fact, a Darwinian model could be applied to HIV dynamics, with the continuous production of variants and the continuous selection of the "fittest" virus.

With the daily production of perhaps 10(to the ninth power) to 10(to the tenth power) virons, a mutation rate of 3x10(to the third power) per nucleotide per replication cycle, and the HIV genome being approximately 10,000 nucleotides in length, any single mutation could exist before any drug is introduced. The relative levels of mutants is probably determined by three concurrent factors: the forward mutation frequency (i.e., the number of copying errors on a particular codon), the cost of the mutation (i.e., the replicative capability of the mutated virus), and the age of the quasispecies (i.e., how long ago, in the individual patient, the viral population with a particularly resistance mutation was generated).

It is clear today that the appearance of genetic variants is a function of the number of cycles that take place during infection, and that combination therapy suppresses HIV replication to undetectable levels can delay or prevent the emergence of resistant strains. In fact, variants that are resistant to three drugs (i.e., that harbor many contemporary mutations) are unlikely to pre-exist, the development of new mutations depends on "new viral cycles, and, often, high-level resistance requires the presence of multiple mutations. Therefore, we may conclude that the more effectively HIV is suppressed the few opportunities there will be for new mutations or emerge. That is why it is recognized that the goal of antiretroviral therapy should be to suppress HIV replication at least to levels undetectable by the more sensitive HIV RNA assays.

However, because this goal might not be attainable in all patients, the tendency of HIV to generate drug-resistant variants may remain the major factor limiting the ability of antiretroviral therapy to fully control HIV replication and completely reverse the natural history of the disease.

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