Resistance to nRTIs

The International AIDS Society–USA, the US Department of Health and Human Services, and European guidelines recommend antiretroviral resistance testing for primary HIV infection and in cases of treatment failure. These guidelines also recommend or encourage consideration of testing in chronic infection of less than 2 years’ duration. US surveillance data indicate that transmission of resistant virus is a substantial and growing problem. Data gathered in 2003 and 2004 from 787 newly diagnosed antiretroviral therapynaive subjects from 89 sites in 6 states indicate the presence of resistance to at least 1 antiretroviral drug class in 14.5% of cases, including resistance to nucleoside analogue reverse transcriptase inhibitors (nRTIs) in 7.1%, nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs) in 8.4%, protease inhibitors (PIs) in 2.8%, and 2 or more classes in 3.1% (Bennet, CROI, 2005). Although it was once believed that acquired resistant strains would be quickly replaced by wild-type virus, it has become clear that resistant virus persists for prolonged periods. This phenomenon probably reflects the fact that only the resistant strain is transmitted, so that reversion to wildtype virus requires “back mutation,” a more time-consuming process than the selection of pre-existing wild-type strains that occurs in treatment-experienced patients. In one recent study, the average time to reversion to wildtype virus after identification of resistant strains among newly infected patients was 375 days for NNRTI-resistant virus and 362 days for nRTI-resistant virus; no reversion was seen with up to 2 years of follow-up for PI-resistant virus (Little, CROI, 2004). For this reason, there is growing support for resistance testing in chronically infected, treatment-naive patients. However, despite the persistence of mutant virus after infection, the diagnostic yield of resistance testing is highest with earlier testing. It is therefore recommended that resistance testing be performed at the time of HIV diagnosis, regardless of the current need for therapy; it can be assumed that transmitted resistance mutations will still be present, even if not detected in the circulation, when therapy is eventually initiated. Genotypic analysis is preferred over phenotypic testing in this setting, primarily because it is more sensitive for the detection of mixtures of susceptible and resistant virus, which would be expected if reversion to wild-type had begun to occur at the time of testing. Genotyping is also faster and less expensive.