Low-level resistance linked to treatment failure: a role for more sensitive testing for naive patients
Simon Collins, HIV i-Base
Several studies have already shown that low level NNRTI resistance is linked to clinical failure and that both the low genetic barrier to NNRTI resistance and the limits of sensitivity of standard genotype tests pose a challenge for detecting mutations in treatment naive patients who may have been infected with NNRTI-resistant virus.
A study from Johnson and colleagues investigated the impact of low-frequency drug-resistant viruses on antiretroviral treatment success, and any association existed between minority variants with resistance-associated mutations at baseline and poor virological suppression.
The group performed baseline resistance testing on treatment-naive patients who participated in GSK trial four years ago using abacavir/3TC/efavirenz. They looked for K103N, Y181C, and M184V using real time PCR-based assays sensitive to mutations present at ~ 0.5% (compared to ~ 20% with standard tests) in 69/70 subjects who had virological failure (>50 RNA copies/ml) by 48 weeks) and a control group of 69 patients with fully suppressed virus.
Standard virus population genotyping only identified K103N or M184V at baseline in 3 people. Real time PCR testing detected these mutations, plus previously unidentified resistance-associated mutations at low frequencies (~ 0.616%) in 7 other individuals.
All 10 people with detectable K103N, Y181C, or M184V at baseline were virological failures, and none were detected in the control group. The correlation between low-frequency resistance and virological failure was significant (P=0.005).
Of those with detectable treatment-relevant mutations at baseline, 2/10 never suppressed, 4/10 failed within 2 months, 2/10 failed by month 4, and the remaining two failed by month 6 of treatment. Three of four persons with available genotypes at failure had the same mutations as low-frequency variants at baseline.
The authors concluded that the clinical significance of drug-resistant viruses at frequencies <20% was demonstrated by this strong association with virological failure, and was independent of baseline viral load.
Current prevalence of transmitted resistance, and the high subsequent cost of first-line treatment failure, have lead to recommendations in both the UK and US management guidelines, for resistance testing prior to starting treatment in naive patients.
In practice this means including resistance testing on diagnosis, or storing a sample for later use, in order to have an optimum chance of not missing mutations that revert to wild type, between diagnosis and the date that treatment is eventually started.
Other studies have shown limitations of standard genotyping in detecting NNRTI resistance in treatment experienced patients , but this study is particularly important for its implications for naive patients.
- Johnson JA, Li J-F, Wei X, et al. Baseline detection of low-frequency drug resistance-associated mutations is strongly associated with virological failure in previously antiretroviral-naive HIV-1-infected persons. XV International HIV Drug Resistance Workshop, Sitges, Spain, July 2006. Abstract 46.
- Mellors J et al – Low frequency non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants contribute to failure of efavirenz-containing regimens in NNRTI-experienced patients with negative standard genotypes for NNRTI mutations. XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003. Abstract 134. See report in HTB August/September 2003.