The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs

Abstract

The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.

Figure 1

Subtype-specific poly-A nucleotide motifs lead to template pausing under pressure with thymidine analogues that favor K65R selection in subtype C and D67N selection in subtype B. Depiction of the template-based propensity of subtype C versus B viruses to develop the K65R mutation that is associated with broad cross-resistance among multiple members of the NRTI family of drugs. The codons located at positions 63, 64, and 65 in subtype C RT seem to be critically involved in the preferential development of K65R in subtype C. d4T: stavudine, ddI: didanosine, ABC: abacavir, TDF: tenofovir. It should be noted that the use of stavudine in particular has been shown to yeild K65R in subtype C infections with high frequency. Regimens that are based on the use of TDF and ABC, among other drugs, can help mitigate the development of the K65R mutation.