HIV-1 Genotyping and RAMs
We hypothesized that archived or recently selected RAMs could impair ART efficacy in pharmacologically hard-to-reach anatomic sites (such as the CNS) thus increasing CVE risk.
The type and prevalence of plasma and CSF RAMs in RT in participants with and without CVE are reported in Fig.2. M184V/I was the most common being detected in plasma in 37.2 % and 19.3% of participants with and without CVE (p=0.005). Similarly, in CSF M184V/I was detected in 42.8% and 16.7% of participants with and without CVE (n=63; p=0.026).
At LP, 28 participants with CVE (54.9%) were on ART affected by one or more of the RAMs in RT and/or PI gene, while this was the case for 47 participants without CVE (18.9%, OR 5.232 [2.769-9.887], p<0.001). After accounting for plasma HGRT, the median number of fully active ARVs was significantly lower, but the change had relevant effect size in participants with CVE only (Fig.3B). Adjusting by HGRT, the median CPE score was lower in both groups, but the change had relevant effect size in the CVE group only (Fig.3C). CVE risk decreased by almost 30% per each point increase in HGRT-adjusted CPE score (OR 0.73 [0.62-0.86], p<0.001).
Among the remaining participants with CVE and ARVs unaffected by HGRT (n=23), 3 more subjects were on atypical mono/dual regimen: boosted-darunavir, raltegravir plus boosted-lopinavir, and fosamprenavir plus raltegravir. Therefore, after accounting also for atypical regimens, 31 (60.8%) and 52 (20.9%) participants with and without CVE were on functional or atypical mono/dual regimens which significantly associated with increased risk of CVE (OR 5.872 [3.097-11.134], p<0.001; Fig.3). The presence of plasma RAMs in PT did not contribute relevantly to this association, since results did not change after excluding the 2 cases of isolated RAMs in PT affecting current ART from the analysis (data not shown).
The substitution of CPE score and plasma RAMs in RT with HGRT-adjusted CPE score as covariate at multivariable modelling supported an independent association between CVE and the impairment of ARVs within the CNS mediated by the resistance phenotype (aOR 0.60 [0.48-0.75], p<0.001; Supp.Tab.3).
Sensitivity analyses among participants with VL<50 cp/mL were in line with the previous results as the associations between CVE and being on ART regimens affected by plasma RAMs in RT (OR 5.742 [2.622-12.574], p<0.001), being on HGRT-related functional or atypical mono/dual regimens (OR 6.089 [2.799-13.427], p<0.001) and with HGRT-adjusted CPE score were retained (OR 0.77 [0.63-0.94], p=0.009).