Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case–control study using centralized ultrasensitive 454 pyrosequencing

Abstract

ObjectivesIt is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART.MethodsThis Europe-wide case–control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%–25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression.ResultsTwo hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35–5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76–6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12–5.18, P = 0.024). A dose–effect relationship between virological failure and mutational load was found.ConclusionsPre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

High levels of pre‐treatment HIV drug resistance and treatment failure in Nigerian children

“…However, this is only the first paediatric study on PDR in Nigeria, the country with the second highest number of children living with HIV in the world, and our findings urge further research on PDR in other parts of the country. In addition, we cannot exclude the presence of minority variant drug resistance mutations in our cohort, while this has been shown to be associated with an increased risk of virological failure [29,30]. Finally, the children's age ranged from 0 to 12 years, which makes comparison of PDR with other studies harder, as mutation-harbouring variants may have waned to below the assay threshold in older children [23,31].…”

HIV-1 drug resistance and resistance testing

“…Within the NRTI class, the rate of reversion is more variable: M184V usually fades within one year; T215FY also fades rapidly; but T215 revertants persist for more than ten years (Castro et al, 2013; Jain et al, 2011). It is because of this tendency to fade to lower levels over time that the rates of detectable TDR are higher in recently compared with chronically infected patients, and that studies using more sensitive methods for detecting low-abundance drug-resistant viruses (see section on Diagnosis and Management of Drug Resistance) will detect higher rates of TDR than those using SGRT (Buckton et al, 2011; Cozzi-Lepri et al, 2015; Ellis et al, 2009; Goodman et al, 2011; Metzner et al, 2014). …”

HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

“…In some studies, a dose effect of the frequency or mutational load was shown [63,64 ]. The clinical relevance of NNRTI resistant minority variants has not consistently been confirmed, and has not been demonstrated for other first-line regimens, such as those containing integrase or boosted protease inhibitors, therefore guidance on the use of deep sequencing is still lacking.…”