HIV This Week

Johnson JA, Li J-F, Wei X, Lipscomb J, Irlbeck D, Craig C, Smith A, Bennett DE, Monsour M, Sandstrom P, Lanier ER, Heneine W. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment–naïve populations and associate with reduced treatment efficacy. PLoS Medicine July 2008(5); 7:e158

Transmitted HIV-1 drug resistance can compromise initial antiretroviral therapy (ART); therefore, its detection is important for patient management. The absence of drug-associated selection pressure in treatment-naïve persons can cause drug-resistant viruses to decline to levels undetectable by conventional bulk sequencing (minority drug-resistant variants). They used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naïve persons and assess the clinical implications of minority drug-resistant variants. Johnson et al performed a cross-sectional analysis of transmitted HIV-1 drug resistance and a case control study of the impact of minority drug resistance on treatment response. For the cross-sectional analysis, they examined viral RNA from newly diagnosed ART-naïve persons in the US and Canada who had no detectable (wild type, n=205) or one or more resistance-related mutations (n=303) by conventional sequencing. Eight validated real-time PCR-based assays were used to test for minority drug resistance mutations (protease L90M and reverse transcriptase M41L, K70R, K103N, Y181C, M184V, and T215F/Y) above naturally occurring frequencies. The sensitive real-time PCR testing identified one to three minority drug resistance mutation(s) in 34/205 (17%) newly diagnosed persons who had wild-type virus by conventional genotyping; four (2%) individuals had mutations associated with resistance to two drug classes. Among 30/303 (10%) samples with bulk genotype resistance mutations they found at least one minority variant with a different drug resistance mutation. For the case-control study, they assessed the impact of three treatment-relevant drug resistance mutations at baseline from a separate group of 316 previously ART-naïve persons with no evidence of drug resistance on bulk genotype testing who were placed on efavirenz-based regimens. Johnson et al found that 7/95 (7%) persons who experienced virologic failure had minority drug resistance mutations at baseline; however, minority resistance was found in only 2/221 (0.9%) treatment successes (Fisher exact test, p < 0.0038). These data suggest that a considerable proportion of transmitted HIV-1 drug resistance is undetected by conventional genotyping and that minority mutations can have clinical consequences. With no treatment history to help guide therapies for drug-naïve persons, the findings suggest an important role for sensitive baseline drug resistance testing.

Editors’ note: Conventional bulk sequencing resistance testing detects resistant viruses when they start to reach the level of 20% of all HIV viruses in an infected person. It may miss the presence of minority resistant viruses in up to 17% of newly diagnosed antiretroviral treatment-naïve persons. However, this study using highly sensitive PCR testing revealed that only 7% of those who experienced antiretroviral treatment (ART) failure, in retrospect, had evidence of undetectable viral resistance at baseline. Nevertheless, concerted efforts are needed to keep first-line ART as effective as possible and to prevent HIV transmission, whether from ART-experienced or ART-naïve people.